GENERAL  PATHOLOGY 

AN   INTRODUCTION   TO 
THE  STUDY  OF  MEDICINE 


GENERAL  PATHOLOGY 

An  Introduction  to  the  Study  of  Medicine 

BEING  A  DISCUSSION  OF  THE  DEVELOPMENT 
AND  NATURE  OF  PROCESSES  OF  DISEASE 

BY 

HORST  OERTEL 

Strathcona  Professor  of  Pathology  and  Director  of  the  Pathological  Museum 

and  Laboratories  of  McGill  University   and  of  the  Royal 

Victoria  Hospital,  Montreal,  Canada 


NEW  YORK 

PAUL  B.  HOEBER 

1921 


* 


COPYRIGHT,   1921 
By  PAUL  B.  HOEBER 


Published,  June  1921 


Printed  in  the  United  States  oj  America 


THE  FOLLOWING  PAGES, 
A   RECORD  OF  THE  COMBINED  EFFORTS  OF  ALL  NATIONS  TO 

ARRIVE  AT  THE  TRUTH 
IN  ONE  BRANCH  OF  SCIENCE, 

ARE  DEDICATED  TO 

THE   PRINCIPAL,   GOVERNORS, 

MEDICAL  FACULTY 

AND 
STUDENTS 

OF 

MCGILL  UNIVERSITY, 
AT   ITS  ONE  HUNDREDTH  ANNIVERSARY. 

Vivat,  Crescat,  Floreat! 


451511 


FOREWORD 

AN  effort  has  been  made  in  the  following  pages  to  bring  together, 
in  what  I  hope  is  a  concise  and  at  the  same  time  comprehensive, 
connected  and  readable  form,  those  facts  and  considerations 
upon  which  modern  pathology  rests. 

Care  has  been  taken  to  impress  upon  the  reader  that  path- 
ological processes  are  not  to  be  regarded,  as  they  often  enough 
are,  as  a  personal  conflict  in  which  man  defends  himself  by  a 
special  endowment  with  purposeful  processes  of  defense. 

Pathological  definitions  and  conceptions  unfortunately  still 
abound  in  metaphysical  and  teleological  ideas,  even  though  it 
is  sixty-two  years  after  Virchow's  effort  to  lift  pathology  to  the 
rank  of  other  sciences. 

Thus  the  student  is  easily  misled  in  his  conceptions  of  patho- 
logical processes  and  he  frequently  separates  what  he  has  learned 
in  biology  and  physiology  from  his  pathological  studies  and  ideas. 

My  purpose,  therefore,  was  to  convey  to  my  readers  that 
pathology  must  be  approached  within  the  frame  of  modern 
biology,  and  that  in  the  study  of  disease,  no  less  than  in  the  study 
of  health,  scientific  vision  is  possible  only  if  we  divest  ourselves  of 
all  metaphysical  and  teleological  conceptions  of  use,  harm,  defense, 
vital  forces,  conscious  purpose,  etc.,  and  treat  pathological 
processes  entirely  as  expressions  of  physico-chemical  laws. 

We  must,  in  other  words,  with  Kant,  lay  down  the  rule  that  the 
mechanical  method,  by  which  natural  phenomena  are  brought 
under  general  laws  of  causation  and  so  explained,  and  without 
which  there  can  be  no  proper  knowledge  of  nature  at  all,  should  in 
all  cases  be  pushed  as  far  as  it  will  go,  for  this  is  the  principle  of 
"determinant  judgment."  In  those  cases  in  which  this  is  insufficient 
and  in  which  we  accept  purposiveness,  we  must  remain  conscious 
that  this  purposiveness  is  not  identical  with  the  metaphysical 
conception  of  a  purpose  residing  outside  of  the  organism  itself, 

vif 


viii  FOREWORD 

but  meant  in  so  far  as  it  relates  to  the  cause  and  effect  in  the  or- 
ganism by  which  it  brings  together  the  required  matter,  forms  it 
and  puts  it  in  its  appropriate  place.  This  is  an  internal  purpose, 
not  a  means  to  other  ends  in  which  purposiveness  is  relative  and 
its  cause  external.  It  is  a  heuristic  principle. 

My  second  aim  was  to  furnish  to  the  reader  an  appreciation  of 
present  ideas  by  tracing  their  historic  development.  The  history 
of  a  science  is  an  essential  part  of  it,  and,  should  be  presented, 
not  as  a  simple  recital  of  sequences,  but  in  the  bearing  and 
influence  which  one  step  of  thought  exerts  upon  the  next.  This 
possesses  not  only  great  educational  value,  but  is  the  only  way 
of  arriving  at  proper  valuation  and  understanding  of  current 
ideas,  and  furthermore  cultivates  a  critical  judgment  for  the 
future. 

My  third  purpose  was  to  visualize  as  much  as  possible  patholog- 
ical occurrences,  and  therefore  great  emphasis  has  been  put 
on  the  anatomic-histological,  formal  side  from  the  dynamic 
standpoint. 

Lastly,  I  have  thought  it  essential  to  include  a  somewhat  more 
extensive  discussion  of  certain  subjects,  (e.  g.  heredity  and  disposi- 
tion), than  is  usually  devoted  to  them  in  textbooks  of  pathology. 
This,  I  think,  is  justified  by  their  great  pathological  importance. 

The  instruction  in  pathology*  as  at  present  pursued  at  McGill 
University  is  preceded  by  a  course  in  general  cell  physiology,  in 
which  the  fundamental  physical  and  colloidal  phenomena  of 
normal  cell  life  are  discussed,  so  that  the  course  in  pathology  may 
follow  in  its  footsteps  and  presupposes  knowledge  of  the  normal. 

The  chapter  on  bacteria  and  infection  is  not  intended  to  take 
the  place  of  textbooks  of  bacteriology,  but  those  parasitic  types 
have  been  selected  which  seemed  to  serve  best  as  examples  of 
pathogenic  actions  and  their  relations  to  processes  of  immunity. 
For  the  same  reason  matters  of  technique  are  not  fully  presented. 

In  order  to  keep  the  volume  within  reasonable  limits  and  not  to 
confuse  the  reader,  I  have  omitted  an  extensive  bibliography. 
For  the  same  reasons  controversial  matter  has  been  reduced  to 
what  appeared  a  necessary  minimum.  The  book  is  intended  as 
an  introduction  and  general  outline  of  the  subject.  It  is  difficult 


FOREWORD  ix 

to  strike  always  the  proper  course  in  these  regards.  Illustrations 
have  been  omitted,  because  the  emphasis  has  been  put  on  dis- 
cussion of  the  nature  and  development  of  pathological  process 
and  it  is  assumed  that  laboratory  experience  will  supplement  the 
use  of  the  book. 

My  thanks  are  due  to  Professors  Lloyd,  Willey,  Tait  and  Bruere 
of  McGill  for  much  valuable  information.  The  ever-willing  kind- 
ness of  the  Governors,  the  Superintendent,  Mr.  H.  E.  Webster, 
and  of  my  colleagues  on  the  Staff  of  the  Royal  Victoria  Hospital, 
to  put  at  my  disposal  its  rich  material,  has  been  of  considerable 
help  in  the  preparation  of  this  volume.  To  the  publisher  I  owe 
thanks  for  unselfish  interest  and  speedy  publication. 

My  thanks  are  also  due  to  my  personal  staff,  especially  Drs. 
Crowdy  and  Gross. 

Should  this  attempt  meet  with  friendly  reception,  I  contemplate 
a  second  volume  on  the  diseases  of  special  organs  and  systems. 

H.  O. 

McGiLL  UNIVERSITY,  MONTREAL. 
March,  1921. 


PREFACE 

IT  is  the  custom  to  commence  the  study  of  a  science  with  a  defi- 
nition of  its  scope  and,  in  a  manner  not  unlike  that  of  the  actio 
finium  regundorum  in  Roman  law,  to  draw  boundary  lines  between 
it  and  its  neighbors. 

Such  a  method  of  approach  is  an  imperfect  one  and  leads  to 
erroneous  concepts,  for  a  definition,  in  order  to  be  exact,  must 
repeat  the  whole  matter  of  a  subject  and  endeavor  to  systematize 
it;  but  to  repeat  the  whole  contents  of  a  science  in  a  definition  is 
manifestly  impossible,  and  it  is  equally  impossible  to  isolate,  by 
sharp  boundary  lines,  one  branch  of  science  from  another. 

The  mental  and  moral  disciplines  are  in  a  somewhat  better 
position  in  this  respect,  for  being  a  product  of  the  mind,  they  deal 
with  the  mediate — a  purely  created  world.  Thus,  for  example,  in 
law  or  in  mathematics  more  or  less  permanent  agreement  of  cer- 
tain values  may  be  reached  and  these  may  then  be  readily  classified. 
But  in  the  study  of  biology  we  are  confronted  by  reality — the 
immediate  world.  All  biological  sciences  deal,  therefore,  with  phe- 
nonema  and  processes  of  life  directly.  These  are  so  intimately 
connected,  related,  dependent  upon  each  other  and  are  so  elastic, 
that  strict  limitations  and  separations  are  not  possible.  Influenced 
by  innumerable,  often  unknown  conditions,  processes  of  life  defy 
strict  classification  and  codification.  It  is  only  the  finished,  dead 
subject  which  may  be  so*  treated.  But  our  knowledge  and  views 
regarding  these  processes  are  constantly  changing  and  fluid.  And 
how  many  times  is  one  subject  treated  by  more  than  one  science? 
True  specialization  consists  in  focusing  all  available  rays  of  light 
upon  a  matter.  In  fact,  it  is  only  when  all  boundary  lines  have 
vanished  that  we  obtain  true  scientific  vision. 

In  Lord  Bacon's  words:  "Let  this  be  the  rule  that  all  partitions 
of  knowledge  be  accepted  rather  for  lines  and  veins  than  for  sec- 
tions and  separations."  Or  as  a  great  historian,  Gibbon,  puts  it: 

xi 


xii  PREFACE 

"The  roots  of  all  intellectual  departments  are  interlaced,  although, 
as  in  a  forest,  every  one  appears  at  first  sight  isolated  and 
separate." 

These  difficulties  confront  us  at  once  in  an  attempt  to  define 
pathology  and  to  draw  boundary  lines  between  it  and  its  nearest 
neighbor,  physiology.  For  while  we  may  say  that  pathology  is  the 
science  of  disease,  the  more  thoroughly  we  investigate  this  appar- 
ent distinction  between  health  and  disease  the  more  we  become 
convinced  that  essential  differences  between  health  and  disease 
do  not  exist.  "If  we  reflect,"  says  Goethe,  "upon  our  own  life, 
we  rarely  find  ourselves  well,  physically  and  mentally:  we  are  all 
suffering  from  life." 

The  same  material  and  forces  and  the  same  processes  underlie 
health  and  disease.  Only  their  relations  and  relative  importance 
differ.  Thus,  in  the  development  of  the  embyro  and  in  the  post- 
natal progressive  and  regressive  evolutionary  changes  which  shape 
and  characterize  the  various  age  periods  from  birth  to  old  age  are 
found  the  physiological  prototypes  of  all  pathological  processes. 
But  they  remain  physiological  by  their  orderly  restriction  within 
the  general  individualistic  evolution.  It  is  the  loss  of  orderly  corre- 
lation, the  breaking  of  the  ensemble  by  the  exaggerated  value  of 
one  or  the  other  part  in  relation  to  the  rest  that  constitutes  patho- 
logical life  and  leads,  by  upset  of  the  normal  evolution,  to  death. 

"Disturbances  in  relativity  of  values"  is,  therefore,  the  first  and 
most  important  principle  of  pathological  occurrences.  For  these 
reasons  we  cannot  express  our  conception  of  disease  by  a  short, 
concise  formula.  We  can  form  an  accurate  estimate  of  this  con- 
ception only  by  tracing  the  history  of  our  ideas  of  disease;  for  a 
proper  appreciation  of  present  ideas  is  only  possible  by  following 
the  evolution  of  human  thought. 

The  division  of  health  and  disease  was  primarily  based  on  sub- 
jective (simple  personal)  observations.  It  was  the  altered  feeling, 
the  pain,  the  dis-ease,  which  first  drew  attention  to  pathological 
states.  Amongst  primitive  peoples  this  physical  state  of  pain  and 
ill  feeling  was  connected  with  the  experiences  of  corporal  punish- 
ment, and,  as  the  infliction  of  this  punishment  could  not  be 
traced  to  visible  beings,  it  was  attributed  to  invisible  beings,  gods, 


PREFACE  xiii 

demons,  evil  spirits.  Thus  resulted  the  early  and  close  relation 
between  medicine  and  religion. 

Even  the  first  reflective  thought  in  medicine  was  most 
impressed  and  guided  by  subjective  factors  and  symptoms. 
Of  these  certain  body  fluids  early  attracted  attention  on  account 
of  the  frequency  with  which  their  disturbances  are  apparent  in 
various  diseases.  These  are  blood,  mucus,  yellow  and  black  bile. 
Blood,  mucus  and  bile  were  readily  recognized  by  the  flow  of 
blood  from  wounds,  ulcers,  etc.,  of  mucus  from  the  nose,  mouth, 
throat,  and  bile  by  its  appearance  and  taste  in  vomit.  The  black 
bile  is  somewhat  problematic;  it  was  regarded  as  the  product  of 
the  spleen.  These  four  body  fluids,  or  humors,  were  supposed  to 
combine  in  certain  proportions  and  to  constitute  the  normal 
make-up  of  the  body.  Their  normal  mixture  was  termed  crasis. 
Disturbances  of  the  mixture  produced  dyscrasis  of  various  types 
and  thus  accounted  for  the  different  diseases. 

These  were  the  teachings  of  Hippocrates,  the  celebrated  Greek 
physician,  born  on  the  Island  of  Cos  about  460  B.C.,  and  of  Galen, 
D.A.  130  to  200,  of  Greek  derivation,  but  practicing  in  Rome.  The 
authority  of  this  teaching  controlled  medical  ideas  not  only  of  its 
own  time,  but  throughout  the  Middle  Ages  and  even  to  modern 
periods  of  pathological  thought.  It  was  known  as  humoral  patho- 
logy, inasmuch  as  it  regarded  disturbances  of  body  fluids  as  the 
essence  of  all  diseases. 

The  almost  slavish  adherence  to  humoral  pathology  and  the  lack 
of  progress  in  medicine  up  to  the  sixteenth  century  was  due  to  the 
general  belief  in  authority,  and  also  during  the  early  periods  of 
the  Christian  era  to  the  abhorrence  of  bodily  ills  as  works  of  devils 
and  demons.  Attention  became  centered  around  mental  and 
spiritual  uplift,  and  the  body  was  looked  upon  with  horror  as  the 
work  and  property  of  the  devil.  Treatment  consisted,  therefore, 
largely  of  exorcism — driving  out  of  malign  spirits  and  demons. 
"We  are  born,"  laments  St.  Augustine,  "inter  urinas  et  jxces" 

A  revolt  against  the  blind  following  of  Hippocrates  and  Galen 
was  inaugurated  by  Paracelsus  (Theophrastus  Bombastus  von 
Hohenheim,  1493-1541).  Paracelsus  formulated  a  much  broader 
conception  of  the  nature  of  disease  as  an  abnormal  process  of  life 


xiv  PREFACE 

which  results  from  disturbed  chemical  changes.  According  to  him 
life  is  dependent  upon  a  personal  principle,  "the  Archseus,"  which 
resides  in  the  stomach  and  which  separates  and  eliminates  useful 
from  harmful  substances.  If  the  Archaeus  is  paralyzed,  harmful 
"acrimonious"  substances  accumulate  in  blood  and  tissues  and 
create  disease.  Based  on  these  views  Paracelsus  was  one  of  the 
first  to  recommend  the  use  of  eliminants,  purges  and  alteratives 
as  drugs. 

The  great  reformation  in  pathology,  as  in  other  spheres  of  human 
knowledge,  came  with  the  period  of  the  Renaissance.  This  impor- 
tant movement,  which,  towards  the  end  of  the  fifteenth  century, 
became  manifest  first  in  Italy  and  then  swept  over  the  whole 
world,  reestablished  three  almost  forgotten  values:  (i)  rejuvena- 
tion of  classic  art,  literature  and  science;  (2)  objective  observa- 
tions; (3)  individuality  and  tolerance  of  free  thought. 

In  medicine,  and  especially  in  pathology,  it  was  ushered  in 
through  Andreas  Vesalius  (1514  to  1564)  by  the  development  of 
anatomy  which  gave  a  sounder  knowledge  than  formerly  existed  of 
the  body  and  the  changes  in  disease.  But  it  was  the  merit  of  Mor- 
gagni  (1682  to  1791)  in  his  great  work,  "De  sedibus  et  causis  mor- 
borum  per  anatomen  indigatis"  (1761),  to  attempt  for  the  first 
time  a  correlation  between  symptoms  of  disease  and  the  ana- 
tomical findings  after  death.  He,  therefore,  was  the  first  who 
attempted  to  give  an  anatomic  explanation  of  symptoms  by 
localizing  diseases  in  definite  organs  of  the  body  or,  as  Virchow 
once  happily  termed  it,  he  introduced  the  anatomical  idea  into 
medicine.  His  great  merit  was  further  to  consider  the  usual  and 
unusual  with  equal  care,  and  thus  he  gave  the  first  objective  basis 
for  the  conception  of  disease. 

However,  knowledge  of  the  nature  of  diseases  still  remained 
very  crude  as  hardly  anything  was  known  of  the  construction  of 
organs  in  health  and  disease.  In  other  words,  while  it  was  recog- 
nized that  certain  gross  anatomical  changes  were  associated  with 
certain  symptoms,  the  nature  of  these  changes,  their  development 
and  their  relation  to  the  symptoms  remained  obscure  and  vision- 
ary. An  advance  in  this  respect  was  made  possible  by  Bichat  (1771 
to  1802),  founder  of  general  anatomy,  who  discovered  that  or- 


PREFACE  xv 

gans  consisted  of  general  and  special  tissues  and  that,  correspond- 
ing to  these,  diseases  produced  general  and  special  tissue  changes. 
Herein  lay  an  important  progress,  for  diseases  were  thus  properly 
regarded  as  anatomical  processes.  This  gave  a  great  impetus  to  the 
study  of  pathological  anatomy  in  relation  to  the  development  of 
diseases  and,  therefore,  also  to  symptoms.  Laennec  and  Corvisart, 
the  great  French  physicians  of  the  early  nineteenth  century, 
stood  directly  on  Bichat's  shoulders,  and  to  this  period  belong  also 
the  fine  clinicians  of  the  English  school,  Bright,  Addison,  Hodgkin 
and  others  who,  by  careful  record  of  progress  in  symptoms  and 
progress  in  anatomical  changes,  drew  the  first  concrete  histories 
of  diseases.  Bright,  especially,  stands  out  as  a  commanding  figure, 
for  no  one  has  ever  excelled  him  in  power  and  accuracy  of  clinical 
and  anatomical  observation. 

A  more  profound  knowledge  of  the  nature  of  diseases  was  laid 
by  Rokitansky  (1804  to  1878),  Professor  in  Vienna,  in  the  thorough 
cultivation  of  pathological  histology,  which  disclosed  the  finer 
microscopic  changes  and  thereby  revealed  the  histogenesis  of 
diseased  processes  in  a  very  accurate  and  detailed  manner. 

But  no  matter  how  much  was  gained  by  the  industry  of  investi- 
gators in  collecting  such  data,  the  nature  of  diseases — their  basic 
principles— ^remained  veiled,  and  dyscrasis  and  disturbed  hypothet- 
ical "vital  forces"  were  still  resorted  to  as  explanations.  Thus 
even  to  the  middle  of  the  nineteenth  century  medicine  lacked  a 
scientific  backbone  and  a  uniform  biological  standpoint.  The 
result  of  this  became  disastrous  to  the  practice  of  medicine,  for 
the  various  hypothetical  ideas  on  the  nature  of  disease,  which  were 
necessarily  all  speculative,  gave  rise  to  opposing  and  debating 
"schools"  of  medicine,  such  as  allopathy,  homeopathy,  polyprag- 
masia,  eclecticism,  Rademacher's  and  Priessnitz'  system  of  hydro- 
therapy,  bleeding  of  the  patient  to  unconsciousness,  mesmerism, 
and  others,  which  were  entertaining  and  edifying  to  their  pompous 
defenders  but  of  no  benefit  to  their  patients  or  to  science. 

Out  of  this  apparently  hopeless  chaos  arose  Virchow  (1821-1902), 
Professor  of  Pathology  in  the  University  of  Berlin.  Virchow  may 
properly  be  named  the  founder  of  modern  pathology;  nay,  much 
more,  his  discoveries  and  ideas  are  so  far-reaching  that  they  extend 


xvi  PREFACE 

beyond  medicine  and  form  the  basic  structure  of  modern  biology. 
Virchow  is  generally  spoken  of  as  creator  of  cellular  pathology. 
What  does  this  mean?  Did  he  discover  cells?  He  did  not.  Cells 
(originally  regarded  as  empty  partitions,  hence  the  name)  had 
centuries  before  Virchow,  been  known  to  exist  and  even  their 
importance  was  fully  recognized  by  Schwann.  Malpighi  (1628- 
1694)  of  Bologna  had  first  seen  them  and  later  the  English 
botanist  Grew.  Trevirannus  already  knew  that  cells  combine  to 
form  tissues  and  Schleiden,  and  especially  Schwann  (1839)  had, 
shown  that  all  living  structures  in  plants  and  animals  are  ulti- 
mately combinations  of  cells  and  that  the  ovum  is  a  cell.  What  then 
was  Virchow's  merit? 

Before  Virchow  the  origin,  derivation  and  functional  significance 
of  cells  had  been  obscure  and  hypothetical.  Thus,  even  Schleiden 
and  Schwann  still  held  that  cells  originated  from  unorganized 
matter  which  precipitated  first  as  a  nucleus  surrounded  by  a  mem- 
brane. Through  this  membrane  matter  diffuses  from  outside  and 
thus  cells  are  formed.  Similarly  in  pathology,  cancer  cells  and 
cells  of  scar  tissue  were  supposed  to  arise  through  "vitalization" 
of  exuded  fibrin,  and  this  was  held  to  explain  the  close  relation 
between  inflammation  and  cancer. 

Virchow,  in  a  celebrated  course  of  lectures  delivered  during  the 
winter  semester  of  1858  in  the  Charite  Hospital  in  Berlin,  de- 
veloped the  following  cardinal  doctrines  of  "cellular  pathology:" 
(i)  the  cell  is  the  unit  of  life;  (2)  all  cells  develop  from  preexisting 
cells  (omnis  cellula  e  cellula);1  (3)  diseases  are  pathological  cell 
changes  and  disturbed  cell  relations;  (4)  anatomical  changes  thus 
produced  constitute  the  disease. 

Thus  he  discarded  all  speculative  and  fantastic  systems  in 
medicine  and  created  the  modern  objective  study  of  disease  and 
the  anatomical  (visual)  conception  of  pathological  processes  as 
cell  changes. 

Whatever  scientific  thought  has  been  produced  since  Virchow 
has  only  enlarged,  never  contradicted,  these  principles. 

While  cells  are  then  properly  regarded  as  the  most  important 

1  This  principle  had  already  been  proclaimed  by  Remak  in  1852  in  regard  to 
the  formation  of  embryonic  cells. 


PREFACE  xvii 

vital  unit,  it  must  be  remembered  that  cells  in  higher  organisms, 
commonly  spoken  of  as  metazoa,  are  not  only  building  material, 
but  stand  in  biological  relation  to  each  other.  It  is  the  merit  of 
Hertwig  to  have  emphasized  this  side  of  higher  cell  life.  For  this 
biological  relation  is  one  of  the  most  important  cell  functions.  It 
shows  itself  in  altruism  and  antagonism  of  different  cell  territories 
and  organs.  This  has  become  most  important  from  the  pathological 
standpoint,  for  diseases  represent  not  only  local  cell  disturbances, 
but  disturbed  biological  cell  relations,  and  these  are  frequently  of 
far  greater  importance  and  consequence  than  the  local  cell  changes. 
The  disturbances  of  internal  secretion,  the  independent  growth  of 
tumor  cells,  the  changes  of  parenchyma  cells  to  new  abnormal  cell 
types  in  inflammations,  are  examples  in  point,  for  their  effect  is  not 
only  local,  but  reflects  generally  on  the  whole  state  of  cells  which 
constitutes  the  individual.  Thus,  disease  of  one  part  means  disease 
of  the  whole  by  upset  of  physiological  balance  and  creation  of 
pathological  relations. 

If,  then,  as  we  have  seen,  it  is  not  possible  to  give  an  exact  and 
all-embracing  definition  of  health  and  disease,  what  are  the  most 
important  fundamental  characteristics  and  outstanding  points  in 
each? 

First,  what  comes  within  the  term  of  health?  By  health  we  under- 
stand relative  stability  in  cell,  tissue  and  organ  structure,  function 
and  coordination.  These  depend  upon  proper  relation  of  stimuli  to 
cell  reaction  and  adjustment  of  cells  to  stimuli. 

Secondly,  what  is  disease?  By  disease  we  understand  the  pro- 
longed loss  of  cell,  tissue  and  organ  stability  and  coordination, 
which  results  from  disturbances  in  the  relation  of  stimuli  to  cell 
reactions  beyond  physiological  adaptation.  It,  therefore,  leads  to 
more  lasting  cell  alterations  and  cell  and  tissue  injury. 

It  is  essential  to  appreciate  that  the  loss  of  stability  must  be 
prolonged  in  order  to  come  within  the  range  of  disease,  for  a  short 
or  temporary  upset  may  still  be  considered  physiological.  For  in- 
stance, when  an  individual  by  severe  muscular  exercise  upsets  his 
heat  regulation  and  even  raises  his  temperature,  he  may  for  a 
short  time  present  the  phenomena  of  fever.  This  is  not  regarded 
as  fever  as  long  as  there  is  a  rapid  return  to  normal  conditions  and 


xviii  PREFACE 

the  production  of  body  heat  is  still  carried  on  by  physiological 
methods.  It  is  in  every  instance  the  more  lasting  loss  of  physio- 
logical stability  and  adaptation  which  marks  a  process  as  patho- 
logical— a  loss  which  leads  to  derangement  and  perversity  of  cell 
activities. 


General  pathology  deals  with  the  processes  of  disease  in  their 
own  general  relations.  It  neglects  the  special  organ  or  anatomical 
structure  in  which  the  disease  occurs;  disregards,  as  much  as  pos- 
sible, the  expressions  of  disease  from  a  particular  locality,  and 
endeavors  to  lay  bare  the  origin,  development  and  common  charac- 
teristics of  diseased  processes. 

It  is  convenient  and  customary  to  treat  general  pathology  under 
two  headings: 

I.  Etiology,  the  causes  of  disease,  which  may  be  divided  into 
two  groups:  i.  The  external  factors.  2.  The  internal  factors.  The 
external   factors   may,  again,  be  subdivided  into  two  divisions: 
(i)   Bacteria  and  infection;  the  higher  parasites.    (2)    Physical 
agents;  heat,  cold,  air,  pressure,  electricity,  light  rays.  Chemical 
agents;  poisons. 

II.  The  Pathological  Processes  themselves.  These,  again,  fall 
under  two  intimately  connected  subjects: 

1.  Pathological  anatomy  and  histology,  or,  the  morphological 
changes  of  disease. 

2.  Pathogenesis,  the  manner  by  which  these  changes  develop, 
and  the  nature  of  the  lesion. 

It  is  to  be  noted  that  pathological  anatomy  and  histology  differ 
from  normal  anatomy  and  histology  in  being  not  only  descriptive 
but  eminently  explanatory  of  the  character  of  a  disease.  For, 
being  representative  stages  of  a  disease  at  a  certain  time,  they  col- 
lectively disclose  the  whole  formal  genesis,  that  is,  the  manner  of 
development  and  the  history  of  a  disease. 


CONTENTS 

BOOK  ONE— ETIOLOGY 
PART  I — THE  EXTERNAL  FACTORS 

SECTION   I — BACTERIA  AND  INFECTION 

CHAPTER  PAGE 

I.  INTRODUCTION.  HISTORICAL.  GENERAL  CONSIDERA- 
TIONS         i 

II.  STAPHYLOCOCCI,     STREPTOCOCCI     AND     BACILLUS 

PYOCANEUS.   .    ....  |;  .   .    1    .   .    .    .    .    .    .     14 

III.  DIPLOCOCCUS  PNEUMONL-E 25 

IV.  DIPLOCOCCUS     INTRACELLULARIS     MENINGITIDIS. 

GONOCOCCUS  AND  MlCROCOCCUS  CATARRHALIS     .       28 

V.  BACILLUS  COLI  COMMUNIS 34 

VI.  BACILLUS  TYPHOSUS 39 

VII.  PARATYPHOID  BACILLI 44 

VIII.  BACILLUS  DYSENTERIC 47 

IX.  CAPSULATED    BACILLI — BACILLUS    LACTIS    AERO- 
GENES — THE  PROTEUS  GROUP 49 

X.  BACILLUS  DIPHTHERIA.  DIPHTHEROIDS 51 

XI.  BACILLUS  TUBERCULOSIS 62 

XII.  THE  BACILLUS  OF  LEPROSY 70 

XIII.  ACTINOMYCOSIS 72 

XIV.  BACILLUS  MALLEI  (GLANDERS) 75 

XV.  ANTHRAX 77 

XVI.  THE  PLAGUE  BACILLUS 82 

xix 


xx  CONTENTS 

CHAPTER  PAGE 

XVII.  THE  TETANUS  BACILLUS.  BACILLUS  OF  MALIGNANT 

EDEMA — BACILLUS  AEROGENES 84 

XVIII.  TYPHUS  EXANTHEMATICUS 90 

XIX.  INFLUENZA 92 

XX.  THE  SPIRILLA 95 

XXI.  THE  PATHOGENIC  PROTOZOA 103 

XXII.  IMMUNITY 108 

Definition  and  classification. — Infection — Acquired  Im- 
munity— Natural  Immunity — Passive  Immunity — 
Anaphylaxis — Theories. 

SECTION    II — PHYSICAL   AND    CHEMICAL    FACTORS    AS   THE    CAUSE  OF 

DISEASE 

XXIII.  TEMPERATURE — HEAT  AND  COLD 137 

XXIV.  AIR  PRESSURE 141 

XXV.  ELECTRICITY,  X-RAYS  AND  RADIUM 143 

XXVI.  POISONS  (TOXICOLOGY) k    ...    147 

PART  II — THE  INTERNAL  FACTORS 

XXVII.  DISPOSITION  AND  IDIOSYNCRASY 151 

XXVIII.  HEREDITY 160 

BOOK  TWO— PATHOLOGICAL  ANATOMY,  HISTOLOGY 
AND  PATHOGENESIS 

I.  INTRODUCTION 173 

II.  PATHOLOGICAL  CHANGES  IN  THE  CELLS  (NUTRITIVE 

DISTURBANCES) 176 

REGRESSIVE  CHANGES — Atrophy — Degenerations — Ne- 
crosis. 

PROGRESSIVE  CHANGES — Hypertrophy  and  Hyperplasia — 
Regeneration — Wound  Healing — Metaplasia — Trans- 
plantation. 


CONTENTS  xxi 

CHAPTER  PAGE 

III.  PATHOLOGICAL  CHANGES  IN  LOCAL  CELL  RELATIONS  2 1 8 

INFLAMMATION — Degenerative — Exudative — Productive — 
Course  and  Terminations — Inflammatory  Tissue  For- 
mation— Conclusions. 

Infective  Granulomata — Tuberculous  Inflammations — 
Syphilitic  Inflammations — Leprous  Inflammations — 
Actinomycotic  Inflammations  —  Glanders  —  Rhino- 
sclerma — Blastomycosis — Infective  Granulomata  of 
Unknown  Etiology. 

TUMORS — General  Characteristics — Metastasis — General 
Histology  and  Diagnosis — General  Constitutional 
Effects — Classification : 

Histoid — Fibroma,  Myxoma,  Lipoma,  Xanthoma,  Chon- 
droma,  Osteoma,  Lymphoma,  Myeloma,  Melanoma 
or  Chromatophoroma,  Myomata,  Leyomyoma,  Rhab- 
domyoma,  Glioma,  Neuroma,  Sarcomata. 
Organoid — Papillomata,    Adenomata,    Cystadenomata, 
Cancers,     Carcinomata,     Hypernephroma,     Chorio- 
epithelioma. 
Endotbeliomata — Angiomata,    Hemangiomata,  Lymph- 

angiomata,  Angiosarcomata,  Mesotheliomata. 
Mixed  Embryonic — Teratoid,  Teratomata,  Embryomata. 
ETIOLOGY  AND  HISTOGENESIS  OF  TUMORS. 
EXPERIMENTAL  STUDY  OF  TUMORS. 

IV.  PATHOLOGICAL  CHANGES  IN  GENERAL  CELL,  TISSUE 

AND  ORGAN  INTERRELATIONS 298 

DISTURBANCES    IN    BLOOD   AND   LYMPH    CIRCULATION — 
Disturbances  in  Blood  Circulation — Pathological  Changes 
in   the  Amount  and  Quality   of  the    Blood — Local 
Changes  in  Blood  Circulation — Thrombosis — Embo- 
lism— Hemorrhage — Shock. 
Disturbances  in  Lymph  Circulation — Edema. 
DISTURBANCES      OF      INTERNAL     SECRETION     AND     OF 
SPECIFIC  METABOLISM — General  considerations — Afunc- 
tion,  Hypofunction,  Hyperfunction — Dysfunction. 
FEVERS   (Febris.    Pyrexia) — Cause  of  Fever  and  of  the 
Rise  in  Temperature — Nature  and  Significance  of  Fever. 

V.  GENERAL  SOMATIC  DEATH 362 

EPICRISIS .    331 

INDEX 333 


BOOK  I 

ETIOLOGY 


Part  I— The  External  Factors 


SECTION  ONE 
BACTERIA  AND  INFECTION  • 


CHAPTER  I 
INTRODUCTION 

HISTORICAL.  Originally  the  source  of  all  infection  (from 
inficere  =  to  contaminate)  was  seen  in  the  air  as  that  common 
medium  which  came  into  most  intimate  contact  with  everything 
and  everybody,  and  so  could  be  regarded  as  the  most  probable 
source  of  infection.  Such  contaminated  air  was  spoken  of  as  miasma, 
which  literally  means  putrid  or  noxious  stain.  This  idea  of  mias- 
matic, air-born  diseases  persisted  until  the  middle  of  the  nineteenth 
century  As  late  as  1860  as  good  an  observer  and  physician  as 
Murchison  still  believed  that  sewer  gas  was  the  cause  of  typhoid 
fever.  When  in  1871  King  Edward  VII,  then  Prince  of  Wales, 
contracted  typhoid  fever  at  Sandringham,  the  chance  escape  of 
sewer  gas  into  his  apartments  was  considered  the  cause.  Explana- 
tion of  sudden  appearance  of  infectious  diseases  and  of  epidemics 
was  found  in  outside  factors,  more  especially  geographical  and 
heavenly  conditions  and  these,  in  certain  favorable  combinations, 
were  supposed  to  form  a  constitutio  epidemica,  and  account  for 
the  outbreak  of  epidemics. 

The  idea  of  infection  was  later  contrasted  with  contagion  after 
it  was  found  that  certain  infections  were  conveyed  directly  from 
man  to  man.  This  became  clear  after  the  frightful  and  interesting 
epidemic  of  syphilis  at  the  end  of  the  fifteenth  century  (Fracastor 
in  1546).  It  is  probable  that  the  Jesuit  Kircher,  about  1660,  was 
the  first  to  observe  lower  types  of  life  in  pus  and  in  material  from 
pest  patients  and  putrefying  plants.  More  definite  were  the  ob- 
servations of  van  Leeuwenhoek,  a  Dutch  lens  maker,  who,  with 
the  aid  of  his  lens,  saw  some  of  the  larger  micro-organisms  in 
decomposing  infusions  of  plants  (1675).  He  spoke  of  these  as 
"animalcules."  He  also,  with  this  aid,  in  1677,  although  priority 


2  GENERAL  PATHOLOGY 

of  this  discovery  was  claimed  by  Nicholas  Hartsocker,  of  Rotter- 
dam, discovered  spermatozoa  in  the  seminal  fluid. 

The  first  ideas  of  a  parasitic  character  of  diseases  were  ad- 
yji'iiced  by<PI;enciz;of  Vienna  in  the  second  half  of  the  eighteenth 
century  (1762),  and  he  already  concluded  that  specific  living  germs 
lyejrc -tlie; ' causes  for  various  infectious  diseases;  that  only  living 
organisms  accounted  for  general  dissemination  of  a  disease  in  an 
individual  and  through  air,  and  that  they  demanded  a  correspond- 
ing specific  therapy.  These  ideas  remained  hypothetical  and 
unsupported. 

But  the  matter  of  infection  did  not  become  fluid  and  real  pro- 
ductive until  Schwann,  in  1837,  demonstrated  that  fermentation 
was  caused  by  living  organisms.  It  was  then  that  similar  organisms 
were  discovered  in  vomit  and  feces,  and  vibrios  in  pus  by  Donne 
(1837).  The  important  observation  of  Bassis  that  a  disease  of 
caterpillars  was  due  to  an  infection  with  a  contagious  fungus  (1838) 
paved  the  way  for  a  similar  conception  of  the  origin  of  diseases 
in  higher  animals.  The  anatomist  Henle,  in  1840  held  that  all 
contagious  diseases  must  be  due  to  living  organisms  (contagium 
vivwri),  and  insisted  upon  certain  requirements  for  recognition  of 
specific  causes  in  infections. 

During  the  earliest  time  of  our  knowledge  of  micro-organisms  the 
question  had  already  been  asked,  "Where  do  these  lowest  forms  of 
life  come  from?"  It  had  been  concluded  that  they  arise  spontane- 
ously as  the  result  of  chemical  changes  in  decomposing  fluids. 
The  Abbe  Spallanzani  (1777)  was  the  first  to  conduct  scientific 
experiments  opposed  to  this  view.  Before  him  Francesco  Redi  had 
already  observed  that  meat  which  was  screened  from  flies  never 
developed  maggots,  but  Spallanzani  showed  that  when  ferment- 
able fluids  were  first  boiled  and  then  corked,  fermentation  did  not 
occur  until  they  were  again  uncorked.  These  experiments  were 
objected  to  as  having  excluded  air  necessary  for  spontaneous 
generation.  But  Schultze  and  Schwann  showed  somewhat  later 
(1836)  that  fermentation  was  also  inhibited  when  air  had  been 
previously  passed  through  sulphuric  acid. 

The  final  and  definite  disproof  of  spontaneous  generation  was 
furnished  by  Hoffmann  (1860),  Chevreuil,  Pasteur  (1861)  and  Tin- 


INTRODUCTION  3 

dall.  (Cohn's  discovery  of  resistant  bacterial  spores  in  1871  ex- 
plained why  sterilization  is  not  always  successful.)  In  the  meantime 
a  better  knowledge  of  minute  organisms  was  obtained  by  Ehren- 
berg  in  1838,  and  especially  by  Cohn,  who  classified  them  and 
recognized  bacteria  as  plants. 

It  was,  however,  the  work  of  Pasteur  which,  although  conducted 
for  other  reasons,  became  of  fundamental  importance  for  bacteri- 
ology and  practical  medicine.  He  demonstrated  that  fermentation 
was  the  result  of  chemical  changes  brought  about  by  the  metabo- 
lism of  living  plants,  the  yeast  cells;  that  the  various  types  of 
fermentation,  as  that  in  butter,  wine,  vinegar,  depended  upon 
specific  organisms  and  that  the  so-called  diseases  of  wine  and  beer 
were  of  organized  nature.  He  further  discovered  (1862)  that  air 
contained  floating  micro-organisms,  showed  them  to  be  the  cause 
of  putrefaction  and,  finally,  that  some  micro-organisms  only  grew 
on  the  exclusion  of  air  (anaerobes).  His  great  merits  in  regard  to 
protective  immunity  in  infectious  diseases  will  be  later  referred  to. 

Pasteur's  investigations  laid  the  foundation  for  Lister's  work  and 
ideas  on  antisepsis.1  Lister  concluded  (1865)  that  decomposition 
and  putrefaction  in  wounds  were,  in  all  probability,  due  to  the 
same  causes  which  initiated  putrefaction  and  decomposition  out- 
side of  the  body.  Again,  the  specificity  in  cause  and  effect  of  dif- 
ferent fermentations  made  specific  micro-organisms  for  the  various 
infectious  diseases  probable.  Thus  since  about  1870,  stimulated  by 
the  German-French  War,  interest  was  aroused  in  the  etiology  of 
wound  infection  and  led  to  the  discovery  of  numerous  organisms 
in  pus  and  inflamed  tissues  (Rindfleisch,  Klebs,  Waldeyer). 

However,  the  relation  of  these  micro-organisms  to  different 
types  of  infections  remained  still  very  doubtful,  as  no  distinguish- 
ing points  could  be  discovered  in  any  of  them,  and  thus  the  conclu- 
sion was  once  more  reached  that  bacteria  were  probably  only 
accidental  contaminations,  or  that  they  occurred  as  secondary 
invaders  and  did  not  concern  the  etiology. 

It  is  here  that  Koch's  work  acquired  the  greatest  importance 
and  laid  the  foundation  of  modern  bacteriology.  We  owe  to  him 

1  His  contemporary,  Keith,  had  already  observed  that  he  obtained  better 
operative  results  with  boiled  and  polished  instruments. 


4  GENERAL  PATHOLOGY 

the  discovery  of  specificity  in,  and  differentiation  of,  micro-organ- 
isms by  culture,  and  their  recognition  by  ingenious  methods.  He 
secured  not  only  the  foundation  for  bacteriological  technique,  but 
recognized  and  isolated  many  important  specific  pathogenic  forms. 
His  first  publication  dealt  with  the  history  and  development  of 
the  anthrax  bacillus  (1875).  It  practically  established  modern 
bacteriologial  technique  and  reasoning.  By  culture  and  inocula- 
tion he  traced  the  anthrax  development,  showed  the  existence, 
propagation,  and  pathogenic  importance  of  the  spores,  and  em- 
phasized the  necessity  of  burying  the  infected  body  in  ground  of 
below  i5°C.  This  was  followed  by  an  equally  important  work  on 
the  infectious  diseases  of  wounds  (1878),  the  discovery  of  the 
tubercle  bacillus  in  1882,  and  of  the  so-called  comma  bacillus  of 
cholera  in  1884. 

Since  the  eighties  of  the  last  century,  when  Koch's  methods  be- 
came available  for  general  bacteriological  practice,  the  discoveries 
in  the  field  of  pathogenic  micro-organisms  have  been  numerous, 
not  only  of  bacteria,  but  of  disease-producing  protozoa,  and  in 
many  instances  the  manner  of  infection  has  been  settled.  As  a  re- 
sult not  only  medicine,  but  also  hygiene,  or  the  prevention  of 
diseases,  has  been  revolutionized  and  put  on  a  definite  bacteri- 
ological basis. 

GENERAL  CONSIDERATIONS.  Bacteriology  may  be  prosecuted 
from  several  standpoints:  as  pure  science;  in  its  relation  to  hygiene; 
and,  in  its  relation  to  pathology.  The  latter  course  will  be  pursued 
in  the  following  pages.  It  treats  of  bacteria  in  their  relation  to 
disease  and,  therefore,  devotes  attention  merely  to  pathogenic 
micro-organisms.  Here  again  two  subdivisions  may  be  made:  first, 
the  study  of  bacteria  themselves  and,  secondly,  the  mechanism 
and  manner  by  which  bacteria  act  upon  the  body  and  by  which 
the  body  reacts  to  them.  This  last  subject  is  treated  under  the 
general  headings  of  infection  and  immunity. 

BACTERIA.  Bacteria  are  the  smallest  and  simplest  forms  of 
life.  They  are  unicellular,  although  occurring  frequently  in  defi- 
nite groups  of  individuals.  They  are  generally  regarded  as  chloro- 
phyliess  plants,  occupying  a  position  between  plant  and  animal 
life.  However,  this  is  doubtful,  for  evidence  exists  to  show  that,  in- 


INTRODUCTION  5 

stead  of  standing  between  plants  and  animals,  they  are  at  the  foot 
of  the  ladder  of  evolution  and  form  a  kingdom  of  their  own.  In 
favor  of  this  view  is  their  apparent  equal  relations  to  plants  and 
animals.  Some  of  the  higher  bacterial  types,  like  the  tubercle  bacil- 
lus, actinomyces,  and  diphtheria  bacillus,  merge  into  the  plant 
order  of  Hyphomyces  and  molds;  others,  like  the  spirilla  of 
cholera,  of  Vincent's  angina  and  of  syphilis,  stand  very  close 
to  the  protozoa.  Thus  it  is  suggested  that  bacterial  evolution  pro- 
ceeded in  two  diverging  branches,  the  first  towards  plant,  the 
second  towards  animal  life.  In  other  words,  bacteria  may  be  taken 
as  representatives  of  the  earliest  elementary  life  which  led  up,  on 
the  one  hand,  to  the  plant,  on  the  other,  to  the  animal  kingdom. 
Bacteria  of  to-day  are,  therefore,  the  remains,  as  it  were,  of  the 
earliest  kingdom  of  life. 

Bacteria  differ  in  size,  shape,  method  of  division,  propagation, 
manner  of  persistence  (spore  formation)  etc.  Morphologically  we 
have  to  consider  (a)  the  individual  bacterial  cell  and  (b)  groups  or 
colonies  of  bacteria. 

(a)  THE  BACTERIAL  CELL.  The  average  size  of  bacteria  is 
2fj,  in  length  and  about  0.5/^1  in  diameter.1  But  there  exist  great 
variations  even  in  one  species.  Some  micro-organisms  are  ex- 
ceedingly small,  only  points,  some  are  even  ultra-microscopic  and 
filtrable  through  a  fine  porous  filter. 

Amongst  bacteria  higher  and  lower  forms  may  be  recognized. 
The  lowest  forms  are  known  as  Schizomycetes,  fission  fungi  (Nae- 
geli,  1860),  in  which  division  takes  place  by  simple  fission.  Of  the 
schizomycetes  three  forms  are  generally  recognized;  coccus:  (ball), 
bacillus  (rod)  and  vibrio  or  spirillum  (spiral),  although  the  latter 
form  is  now  regarded  by  some  as  belonging  to  the  protozoa.  Higher 
types  of  bacteria  are  larger  and  filamentous  and  branching  forms 
and,  therefore,  are  spoken  of  as  hyphomyces.  They  are  closely 
related  to  the  molds.  Other  higher  bacteria  are  spirillar  in  shape 
and,  as  already  stated,  are  closely  related  to  the  protozoa. 

Finer  Bacterial  Structure.  The  internal  structure  of  bacteria  is 
relatively  undifferentiated.  Many  display  a  definite  capsule.  Much 
discussion  has  been  had  on  the  question  of  the  presence  of  a  nucleus. 

1  i M  equals  i  micromillimeter,  or  Hooo  mm.  =  ^25>ooo  of  an  inch. 


6  GENERAL  PATHOLOGY 

It  has  been  asserted  and  denied.  Recent  observations  seem  to 
indicate  that  while  a  definite  nuclear  unit  is  not  demonstrable, 
chromatin  is  irregularly  distributed  through  the  bacterial  body,  and 
that  metachromatic  granules  are  also  present.  The  question  of  a 
cell  membrane  is  also  uncertain.  A  cellulose  envelope,  characteris- 
tic of  vegetable  cells,  is  absent. 

Motility.  Many  bacterial  forms  are  actively  motile,  that  is, 
possess  the  ability  of  translation  in  space.  This  genuine  motility 
must  be  differentiated  from  quivering,  oscillating,  Brownian  move- 
ments, which  are  physical,  surface  tension  phenomena.  Locomotion 
depends  upon  the  presence  of  flagellae — whip-like,  filamentous  ap- 
pendages, which  by  contraction  and  expansion  propel  the  body. 
Growth  and  division  of  bacteria  into  equal  halves  occur  in  one, 
two  or  three  planes  and  by  elongations.  Maturity  of  individuals 
is  almost  immediate. 

Spore  Formation.  So  called  spores  are  means  of  preserving  and 
reproducing  bacteria  by  resistant  forms.  They  are  much  less  sus- 
ceptible to  those  outside  influences,  which  ordinarily  kill  bacteria. 
They  tolerate  heat  (7O°C.-ioo°C.)  and  poisons  to  much  higher 
degrees  for  the  following  reason:  Heat  and  antiseptics  kill  bac- 
teria by  coagulating  the  contents  of  their  protoplasm,  for  they 
contain  considerable  water  and  salts;  but  spores,  being  poor  in 
salt  contents  and  containing  only  hygroscopic  water,  are  much  less 
susceptible  to  coagulation;  being  simply  dry  they  are,  therefore, 
more  resistant.  Spores  are  compact  and  highly  refractive.  They 
stain  with  difficulty.  They  form  in  any  part  of  the  cell,  usually  at 
the  poles  in  the  anaerobes,  and  are  generally  of  the  same  diameter 
as  the  cell.  Occasionally  they  cause  the  cell  body  to  bulge  and  such 
a  spore-bearing  organism  is  known  as  a  clostridium. 

Spores  give  rise  to  new  bacterial  forms  by  growth  from  the  spore 
body.  The  new  organism  escapes  by  breaking  through  the  capsule 
and  then  divides  in  ordinary  fashion.  Spore  propagation  is  more 
frequent  in  bacilli  than  in  cocci.  Occasional  bud-like  constrictions 
in  rods  and  cocci  are  named  arthrospores.  Their  true  spore  char- 
acter is  doubtful. 

Spores  are  formed  under  the  influence  of  unfavorable  environ- 
ment where  the  bacterial  life  is  in  danger.  The  spore  represents  a 


INTRODUCTION  7 

resting  stage  which  preserves  the  organism  during  an  unfavorable 
period.  This  state  may,  in  a  way,  be  compared  to  hibernation  oi 
higher  animals.  Fortunately  many  pathogenic  .bacteria  are  not 
spore  formers,  which  makes  their  destruction  easier.  But  some  of 
the  most  important  and  malignant  organisms  are,  such  as  the 
bacilli  of  anthrax,  tetanus  and  malignant  edema. 

Capsule.  Bacteria  possess  mucoid  coverings  in  the  form  of  a 
transparent  halo.  This  is  sometimes  very  plain  and  these  micro- 
organisms are  then  termed  capsulated.  The  capsule  may  surround 
either  individuals  or  characteristic  groups.  Almost  all  of  them  are 
capsulated  only  in  the  natural  state,  not  in  culture  except  by  special 
methods.  The  capsule  is  a  product  of  the  bacterial  ectoplasm. 
Opinions  as  to  the  nature  and  significance  of  the  capsule  differ: 
some  regard  it  as  protection,  others  as  indication  of  degeneration. 
It  is  certain  that  some  capsulated  micro-organisms  are  very 
virulent. 

(6)  MORPHOLOGY  OF  GROUPS  OF  BACTERIA.  All  bacterial 
forms,  when  suitably  planted,  grow  in  colonies  and  these  exhibit, 
even  to  the  naked  eye,  characteristic  behavior  on  the  culture 
medium.  Gelatine,  agar  and  bouillon  are  the  most  common  media 
used.  On  these  media  the  various  types  of  bacteria  show  differen- 
tial manners  of  growth  and  these  are,  as  Koch  first  pointed  out, 
diagnostic  of  bacterial  species.  Thus  they  may  or  may  not  liquefy 
the  solid  culture  media,  produce  acid  or  alkali,  various  enzymes, 
pigments  and  other  distinguishing  metabolic  products,  derived 
from  their  own  body  or  by  disintegration  of  the  medium.  We  shall 
now  shortly  review  some  of  these  common  characteristics  of 
bacterial  growth  and  life. 

Temperature.  Bacteria  grow  only  within  certain  variable 
temperature  limits.  If  these  are  exceeded,  on  one  or  the  other  side, 
action  and  life  ceases.  Below  the  minimum  temperature,  life  is  not 
destroyed,  but  only  becomes  latent;  high  temperatures,  however, 
lead  speedily  to  disintegration  of  the  bacterial  body.  Between  the 
two  lies  what  is  known  as  the  optimum  temperature  of  growth, 
provided  other  conditions  of  life  and  nutriment  are  also  supplied. 

Bacteria,  like  other  living  beings,  owe  their  existence  to  chemical 
cleavage  processes  by  which  the  high  unstable  molecules  of  the  cell 


8  GENERAL  PATHOLOGY 

protoplasm  are  converted  to  simpler  compounds  by  saturation  of 
affinities.  Thus  energy  is  liberated.  This  self-disintegration  is 
known  as  internal  respiration  (end  product  is  CO2),  and  depends 
upon  the  instability  of  the  plasma.  It  proceeds  apparently  spon- 
taneously, as  in  an  explosive,  but  in  reality  is  due  to  surrounding 
heat  waves. 

The  motion  of  heat  waves  is  necessarily  greater  in  higher  tem- 
peratures and  is  communicated  to  the  unstable  molecules  of  the 
protoplasm,  which  disintegrate  somewhat  like  a  high,  unstable 
pyramid  crumbles  when  exposed  to  the  force  of  the  wind.  Below 
the  point  of  temperature  which  is  required  to  set  heat  waves  in 
motion,  molecules  remain  necessarily  intact,  but  life  also  ceases, 
remaining  latent.  If,  on  the  other  hand,  heat  waves,  as  in  high  tem- 
perature, move  and  act  violently,  the  plasma  is  injured,  because 
restitution  by  synthesis  becomes  impossible.  Hunger,  therefore,  is 
also  a  gradual  destroyer  of  life.  Thus  warmth  is  the  carrier  of  life, 
while  food  sustains  it.  Generally  speaking  the  optimum  tempera- 
ture of  life  for  bacteria  is  about  37°C.,  hardly  ever  above  42°C.  The 
optimum  limits,  however,  are  wide — for  the  pest  bacillus  about 
3O°C.,  while  for  the  bacillus  of  avian  tuberculosis  about  43°C.  Few, 
if  any,  grow  below  2O°C.;  some  (like  the  gonococcus)  not  below 
3O°C.  Some  of  the  non-pathogenic  bacteria  are  exceptions  to  this 
general  rule,  growing  up  to  75°C.  and  at  2o°C. 

Air  and  Oxygen.  Bacteria  are  divided  into  three  groups  as 
regards  behavior  towards  atmospheric  air  and  oxygen. 

1.  Obligatory  aerobes,  needing  air  or  uncombined  oxygen. 

2.  Facultative  or  optical  anaerobes,  which  grow  in  the  presence 
of  air  or  uncombined  oxygen. 

3.  Obligatory  anaerobes,  which  do  not  grow  in  the  presence  of 
air  or  uncombined  oxygen. 

The  first  group  fails  to  grow  and  functionate  when  oxygen  is 
reduced  below  the  optimum  tension.  If  oxygen  is  still  further  de- 
creased, bacteria  are  injured  and  spore  formation  is  prevented. 

To  the  second  group  belong  a  large  number  of  pathogenic  bac- 
teria, such  as  anthrax,  typhoid,  bacillus  coli,  cholera,  bacillus 
aerogenes  capsulatus,  etc.  They  grow  in  the  presence  of  air,  but 
also  may  do  so  on  its  exclusion. 


INTRODUCTION  9 

The  third  group  is  a  very  interesting  one  and  was  brought  to 
light  by  Pasteur.  It  includes  a  number  of  important  pathogenic 
micro-organisms,  such  as  the  bacillus  of  tetanus,  of  malignant 
edema,  etc.,  and  also  many  putrefactive  bacteria.  While  their  life  is 
generally  maintained  on  exclusion  of  oxygen,  they  may  adapt  them- 
selves to  minute  quantities  of  oxygen.  They  do  not  live  by  oxida- 
tion but  derive  their  energy  from  cleavage  (reduction)  processes 
only.  (It  will  be  remembered  that  cleavage  precedes  oxidation,  but 
in  oxidation  oxygen  combines  rapidly  with  cleavage  products  to 
form  the  end-products  (H2O  and  CO2),  thus  liberating  much 
energy.  In  anaerobes,  this  second  step  is  omitted. 

Other  Gases.  Facultative  organisms  and  strict  anaerobes  grow 
well  in  H  and  N.  Many  do  not  grow  in  CO2  at  all;  anthrax, 
bacillus  subtilis,  bacillus  glanders  and  cholera  bacillus  are  quickly 
killed  by  it  and  so  are  others.  H2S  is  also  poisonous. 

Culture  Media.  For  culture  media  organic  foodstuffs  are  em- 
ployed, chiefly  proteids  and  carbohydrates,  the  latter  to  supply 
carbon  and  energy.  The  reaction  of  culture  media  suitable  for  most 
bacteria  is  a  weak  alkalescence.  Culture  media  are  of  very  great 
diagnostic  importance,  for  bacteria  possess  characteristic  manners 
of  growth  and  produce  characteristic  chemical  substances  on  them. 

Culture  media  are  of  very  great  diagnostic  importance,  for  bac- 
teria possess  characteristic  manners  of  growth  and  induce  char- 
acteristic chemical  changes  in  them. 

Products  of  bacterial  growth  are  of  two  kinds:  (i)  Those  resulting 
from  disintegration  of  the  culture  medium;  (2)  those  resulting  from 
bacterial  secretion,  ferments  and  enzymes. 

i.  Reduction  Processes,  (a)  Splitting  O  from  culture  medium 
through  metabolic  products.  (6)  The  formation  of  H2S  from  pro- 
teins and  peptones  in  the  presence  of  nascent  H.  (c)  Reduction  of 
nitrates  to  nitrites,  ammonia  and  free  N  and  the  formation  of 
basic,  alkaloidal  substances  known  as  ptomaines. 

Formation  of  Aromatic  Compounds.  The  most  important  of  the 
aromatic  compounds  is  indol,  which  is  derived  by  certain  bacteria 


from  peptone:  CeH4\          /CN.  It  is  important  diagnostically,  as 


io  GENERAL  PATHOLOGY 

some  bacteria,  like  colon  and  cholera,  are  active  indol  producers, 
while  others,  like  bacteria  of  typhoid,  are  not.  (Easily  demonstrated 
in  broth  culture  by  adding  concentrated  H2SO4  +  o.oi  Sod.  ni- 
trite =  red  color.  More  delicate  is  Ehrlich's  test  with  Paradimethyl- 
amidobenzaldehyde  and  Pot.  sulfate  (Sol.  I.  The  former  4  pts.,  abs. 
ale.  380  pts.,  cone.  HCI  80  pts.  Sol.  II.  Pot.  sulf.  saturat.  watery 
sol.)  5  c.c.  of  I  to  io  c.c.  culture  and  5  c.c.  of  II  =  red  color.) 

2.  Fermentation  and  Enzyme  Formation.  By  fermentation  and 
enzyme  action  is  meant  chemical  decomposition  by  cell  activity, 
either  directly  or  by  a  cell  product,  the  enzyme.  Of  these  actions 
bacteria  possess  a  considerable  number  of  importance,  as  follows : 

(a)  Simple  hydrolytic  cleavage,  in  which  the  source  of  energy  is 
diastatic,  changing  starch  to  sugar,  acid,  H2O  and  CO2. 

(6)  Sugar  splitting,  in  which  bacteria,  like  yeasts,  are  capable  of 
splitting  sugar  into  alcohol  and  CO2,  thus : 

C6H1206  =  2C2H5OH  -f  2C02 

(c)  Formation  of  acids  from  alcohol  and  other  organic  acids: 
It  has  been  known  for  a  long  time  that  bacterium  aceti  converts 
alcohol  to  acetic  acid  by  oxidation.  Acids  are  also  formed  by 
splitting  sugar  or  glycerine.  Higher  alcohols,  like  dulcite  and  man- 
nite,  may  also  be  converted  into  acids  alone,  or  acids  and  gas. 
These  reactions  are  useful  in  the  identification  of  bacterial  species. 
Only  few  bacteria  produce  alkali  reaction  in  culture  media  by  syn- 
thetic processes.  According  to  Theobald  Smith  all  aerobes  or  facul- 
tative anaerobes  form  lactic  acid  from  sugar. 

(d)  Invertive — changing  cane  sugar  to  dextrose. 

(e)  Peptonizing  and  proteolytic — changing  albumen  to  peptone 
and  liquefying  proteids,  especially  gelatine. 

(/)  Coagulating — rennin  action. 

(g)  Splitting  urea— CO(NH2)2  +  2H2O  =  CO3(NH4)2  (Micro- 
coccus  ureae).  Aerobes  produce  alkaline  substances  from  proteids. 

(b)  Nitrification  is  a  very  important  process  for  the  mainte- 
nance of  life  in  nature  and  is  an  excellent  example  of  useful  or  al- 
truistic activity  of  bacteria.  It  represents  the  oxidation  of  ammonia 
to  nitrites  and  nitrates.  This  maintains  the  proper  circulation  of  N 
in  nature,  for  it  puts  it  into  a  form  suitable  for  reconsumption  by 


INTRODUCTION  1 1 

plants  and  thus  counteracts  the  constant  reduction  of  proteids  to 
nitrates,  nitrites  and  ammonia.  Nitrification  is  accomplished  by  a 
special  group  of  bacteria,  knowledge  of  which  we  owe  to  Wino- 
gradsky  and  Warrington.  It  occurs  in  the  soil  and  is  the  work  of 
two  organisms,  one  converting  ammonia  into  nitrites,  the  other 
converting  nitrites  into  nitrates,  as  follows : 

XH  ,OH 

N^H        NA)H— H2O  =  O  =  N— OH 
XH  XOH 

Ammonia  Normal  Nitric  acid  Nitrous  acid 

O 

+  o  =|| 

N— OH 

II 
O 

Nitric  acid 

Nitrates,  thus  formed,  are  taken  up  by  the  chlorophyl  bearing 
plants  and,  in  the  energy  of  sunlight,  are  transformed  into  pro- 
teins with  H2O,  CO2,  phosphates,  etc. 

VARIATIONS  AND  ADAPTABILITY  IN  BACTERIA.  This  subject 
has  been  a  matter  of  active  discussion  in  relation  to  specificity 
and  pathogenicity  of  bacterial  strains. 

In  bacteria,  as  in  other  forms  of  life,  races,  strains  and  even  indi- 
viduals vary,  but  inasmuch  as  bacteria  are  the  simplest  form  of 
unicellular  organisms  without  differentiation,  and  without  any 
nucleus,  dividing  by  fission  only,  they  are  more  open  to  environ- 
mental influences  than  higher  differentiated  multicellular  organ- 
isms of  complicated  construction  which  possess  specific  nucleated 
sex  cells.  In  other  words  the  tendency  to  generic  and  individual 
stability  increases  with  ascending  animal  evolution  (see  later  under 
heredity).  Bacteria,  however,  for  the  reason  just  stated,  adapt 
themselves  to  their  habitat  in  culture  medium,  temperature,  etc., 
to  such  an  extent  that  a  sufficient  deviation  from  the  original 
may  occur  to  impress  us  as  a  new  species.  Whether  this  is  due  to 
the  acquisition  of  new  characters  or  suppression  of  certain  old 


12  GENERAL  PATHOLOGY 

ones,  or  the  survival  of  forms  originally  endowed  with  what  now 
seem  to  be  new  characteristics  of  the  whole  strain,  it  is  not  possible 
to  determine  exactly  and  cannot  be  fully  entered  into  here. 

It  is  sufficient  to  appreciate  that  bacteria  are  variable  and  not 
absolutely  fixed  in  type,  as  was  thought  in  the  early  days  of  bac- 
teriological research.  If  only  slight,  variable  and  temporary  changes 
occur,  often  compared  to  the  ripples  on  the  surface  of  water,  we 
speak  of  them  as  fluctuations;  if,  on  the  other  hand,  the  changes 
are  profound,  definite  and  continuous,  we  speak  of  them  as  sports 
or  mutations.  A  strict  classification  of  bacteria  is,  for  these  reasons, 
very  difficult  and  there  is  often  no  direct  relation  between  cultural 
characteristics  and  pathogenicity.  In  the  diphtheria  bacillus,  for 
example,  we  cannot  tell  whether  we  are  dealing  with  a  mild  or  viru- 
lent strain  from  appearance  and  culture.  We  must  resort  to  inocu- 
lation (biological  test). 

The  subject  of  parasitism  and  saprophytism,  is,  therefore,  inti- 
mately connected  with  the  question  of  variability  and  adaptation, 
and  it  is  customary  to  differentiate  between  three  groups  of 
bacteria: 

1.  Pure  saprophytes,  or  micro-organisms  which  can  under  no 
circumstances  develop  or  grow  in  other  living  organisms.  These 
may,  however,  become  pathogenic  through  their  toxines  as,  for 
instance,  the  bacillus  causing  botulism,  a  form  of  food  poisoning. 

2.  Pure  parasites,  organisms  such  as  the  influenza  bacillus,  the 
meningococcus,  gonococcus,  the  pneumococcus,  etc.,  which  rapidly 
gain  foothold,  thrive  and  spread  in  living  organisms.  They  suc- 
cumb rapidly  outside  of  a  living  body. 

3.  Optional  or  facultative  parasites,  which  under  suitable  condi- 
tions are  infective,  but  may  also  lead  a  saprophytic  existence. 
They  are  not,  as  a  rule,  as  virulent  as  pure  parasites.   However, 
here,  as  in  other  bacterial  properties,  no  sharp  and  permanent 
class  division  can  be  made.  It  has  only  recently  been  well  estab- 
lished that  by  careful,  gradual  cultivation  on  living  organisms, 
ordinary  pure  saprophytes  may  become  converted  into  parasites, 
and  that  by  gradual  sensitization  of  the  host  to  the  micro-organisms 
the  latter  may  acquire  considerable  virulence.  Thus  Charrin  and 
de  Nittis  found  that  the  bacillus  subtilis,  ordinarily  a  harmless 


INTRODUCTION  13 

organism  (saprophyte)  of  the  soil,  may  become  a  parasite,  by 
cultivation  on  blood  media  and  repeated  passage  through  animals. 
Embleton  and  Thiele  showed  that  the  harmless  bacterium  my- 
coides  of  garden  soil,  which  is  ordinarily  destroyed  by  body  heat, 
developed  pathogenic  properties  if  repeatedly  injected  into  animals, 
within  periods  of  a  week  or  ten  days.  Recovering  it  from  animals 
thus  infected,  they  gradually  increased  its  virulence  by  passing  it 
through  other  animals  of  the  same  species.  They  made  another 
very  interesting  observation  in  finding  that  this  acquisition  in 
virulence  was  associated  with  morphological  changes  in  the  bacillus 
itself,  and  that  this  motile  bacillus  lost  its  flagellae,  formed  a  capsule 
and  became  more  stumpy,  so  that  it  could  no  longer  be  differenti- 
ated from  anthrax.  Similar  observations  have  been  made  in  other  bac- 
teria, especially  in  the  large  group  of  streptococci.  Briefly  then, 
we  see  that  by  favorably  timing  inoculation,  animals  may,  by 
sensitizing  them,  be  made  susceptible  to  an  originally  harmless 
organism.  The  latter  acquires  parasitic  properties,  and  may  even 
develop  specific  affinity  for  certain  tissues  and  localities.  However, 
the  conditions  prevailing  in  the  host  are  also  of  greatest  importance, 
for,  as  will  be  more  fully  entered  into  later,  the  disease  which  re- 
sults from  a  successful  infection  is  a  complex  anatomical  change 
in  the  tissues  of  the  host,  into  which  enter  many  other  factors 
besides  the  pathogenicity  of  the  invader.  Moreover,  the  disposi- 
tion of  the  host  towards  an  infecting  agent  is  variable.  This  depends 
upon  external  factors,  such  as  cold,  fatigue,  hunger,  etc.,  and  upon 
as  yet  poorly  understood,  internal  conditions  which  are  collectively 
grouped  as  resistance  (see  under  Internal  Factors  as  Causes  of 
Disease,  page  151).  Thus,  while  the  colon  bacillus,  for  example,  is 
ordinarily  a  normal  saprophyte  of  the  large  gut,  invasion  and 
disease  by  it  are  possible  under  lowered  resistance,  or  as  a  partner 
with  other  organisms. 


CHAPTER  II 

STAPHYLOCOCCI;  STREPTOCOCCI   AND   BACILLUS 
PYOCYANEUS 

STAPHYLOCOCCI.  Cocci  arranged  in  groups  and  bunches.  The 
history  of  infection  with  staphylococci  is  practically  identical 
with  that  of  wound  infections.  Since  1870  investigators  had  seen 
cocci  in  pus,  but  their  significance  became  clear  only  after  Koch's 
methods  and  work  created  a  new  era  in  bacteriology  (1878).  In 
1888  Richet  and  Hericourt  made  the  further  important  discovery 
that  the  serum  of  immune  dogs  (  no  longer  susceptible  to  staphylo- 
coccus  action  after  recovery)  conferred  passive  immunity  when 
injected  into  another  dog.  The  prototype  of  pathogenic  staphylo- 
cocci is  the  Staphylococcus  pyogenes  aureus,  a  pus-producing 
organism,  which  on  culture  brings  forth  a  golden-yellow  pigment. 
The  individual  organism  is  a  small  globe,  about  0.7-0.9/1.  The  size 
varies  according  to  favorable  medium  and  temperature.  It  is 
positive  to  Gram's  method  of  staining.  The  individuals  occur  in 
recent  state  in  pus  in  small  groups  or  bunches  of  two,  or  three  or 
more,  9-10  individuals;  often  four  members  combine  as  tetrads, 
and  even  short  chains  occur. 

The  optimum  temperature  of  growth  is  24°C.  to  28°C.,  but 
much  higher  (42°C).  and  lower  (8°  or  9°C.  even  6°C.)  temperatures 
are  tolerated.  It  is  a  facultative  aerobe,  that  is,  grows  with  O  and 
H.  The  best  reaction  for  growth  is  alkaline,  but  even  a  weakly  acid 
medium  is  compatible  with  it.  It  grows  well  in  broth,  also  in  20 
per  cent,  dextrose  bouillon,  when  its  virulence  is  lessened.  It 
hemolyses  rabbit's  blood.  Growth  is  also  active  in  milk,  which 
slowly  coagulates  with  the  formation  of  lactic  acid.  In  solid  gela- 
tine stab  cultures  it  liquefies  the  medium  from  above  downward. 

On  gelatine  plates,  small  yellowish  points  surrounded  by  a  peri- 
pheral liquefying  zone  appear  after  two  days.  In  from  24  to  60  hours 
there  occur  circular,  flat  depressions  with  sharp,  sometimes  slightly 

14 


STAPHYLOCOCCI  15 

elevated  edges  and  in  the  center  a  yellow  colony  the  size  of  a  pin- 
head.  On  slant  agar  a  supple,  smeary,  yellowish  fiber  is  formed  with 
a  grayish  periphery.  Pigment  is  also  produced  in  abundance  on 
potato,  but  best  and  most  rapid  on  coagulated  blood  serum. 

The  staphylococcus  aureus  is  quite  resistant  to  heat,  to  drying 
and  even  to  burial  for  about  four  weeks. 

Staphylococci  occur  normally  on  the  human  skin,  the  staphylo- 
coccus aureus  not  quite  so  abundantly  as  the  staphylococcus  albus, 
which  does  not  produce  pigment  and,  on  the  whole,  is  much  less 
virulent.  A  number  of  other  types  occur  which  vary  in  slight  cul- 
tural differences  and  in  their  hemolytic  properties.  Besides  being 
abundant  on  the  skin,  they  float  about  in  air.  The  culture  broth 
filtrate  of  Staphylococci  is  toxic  to  other  tissue  cells,  besides  erythro- 
cytes.  The  rabbit  is  the  most  susceptible  of  all  laboratory  animals. 
The  virulence  of  different  strains  is  very  variable,  but  it  may  be 
increased  by  continual  passage  through  animals  of  the  same  species. 
Rabbits  are  usually  killed  by  o.  i  c.c.  of  a  broth  culture  in  four  to 
eight  days  with  the  formation  of  multiple  small  abscesses  in  the 
heart,  kidneys,  joints,  muscles  and  bones.  Sometimes  pericarditis 
and  pneumonia  occur  without  abscesses,  especially  after  large  doses 
which  produce  staphylococcus  septicemia  or  bacteriemia.  Subcuta- 
neous injection  in  rather  large  doses  produces  erysipelas;  injection 
into  the  mediastinum  causes  purulent  inflammation.  The  periton- 
eum seems  less  susceptible,  but  the  eye  is  very  much  so. 

Man  is,  generally  speaking,  more  susceptible  to  staphylococcus 
infection  than  animals.  Here  the  staphylococcus  is  one  of  the  most 
important  and  frequent  pus  and  abscess  producers.  Garre,  experi- 
menting on  himself  by  rubbing  cultures  into  the  skin,  or  after 
subcutaneous  injection,  caused  abscesses  and  furuncles.  Applica- 
tion of  the  bacteria-free,  filtered  broth  to  the  skin  causes  dermati- 
tis. Loci  minoris  resistentia?  (trauma)  are  particularly  exposed  to 
the  staphylococcus  and  thus  the  staphylococcus  frequently  acts 
with  or  follows  infection  by  other  bacteria,  such  as  pneumococci, 
streptococci,  meningococci,  etc. 

The  frequent  localization  of  Staphylococci  in  the  osseous  system 
is  important,  especially  in  the  bone  marrow  of  young,  growing 
individuals.  Here  it  is  the  frequent  cause  of  osteomyelitis.  It  may 


16  GENERAL  PATHOLOGY 

also  give  rise  to  liver  and  subphrenic  abscesses  and  middle  ear 
infections.  In  man,  general  staphylococcus  invasion  in  the  form  of 
a  septicemia  or  bacteriemia  with  verrucose  endocarditis  is  observed 
occasionally,  but  it  is  rare,  except  in  infants.  It  may  then  be  re- 
covered from  the  blood.  (In  blood  cultures  there  is  always  danger 
from  contamination  by  skin  organisms,  therefore  care  should  be 
used  in  interpretation  of  findings.) 

The  staphylococcus  pyogenes  aureus  is  the  typical  pus  and 
abscess  producer.  Its  pus  is  rich  in  polymorphonuclear  leucocytes, 
but  poor  in  fibrin.  As  already  stated  the  organism  takes  advantage 
of  a  primary  injury  or  previous  entrance  of  other  bacteria.  The 
injury  may  be  mechanical  or  chemical.  From  the  original  port  of 
entrance  it  spreads  by  the  lymph  streams  (lymphangitis)  and  then 
by  blood.  Septic  emboli  thus  result  (multiple  abscesses,  pyemia). 

Besides  causing  pus  formation  the  staphylococcus  leads  to  death 
(necrosis)  and  solution  of  the  invaded  tissue  (cell  lysis).  Healing 
of  the  abscesses  occurs  usually  by  a  break  to  the  outside,  rarely  by 
resorption  of  pus.  The  defect  heals  with  formation  of  granulation 
tissue  (see  page  210).  Of  other  less  important  staphylococci,  men- 
tion should  be  made  of  the  staphylococcus  albus  and  the 
staphylococcus  ureae  which  breaks  up  urea  into  ammonium  carbo- 
nate: CO(NH2)2  +  2H2O  =  (NH4)2CO3. 

STREPTOCOCCI  :  Cocci  arranged  in  chains.  The  history  of  strepto- 
cocci commences  with  Ogsten  (1881),  who  was  the  first  to  differenti- 
ate between  staphylococci  and  streptococci  in  pus.  Streptococci 
are  round  cocci  arranged  in  necklace-like  chains.  In  size  the  individual 
coccus  is  about  i/i,  but  this  varies  with  the  culture  medium.  Indi- 
viduals are  often  slightly  flattened  at  the  points  of  attachment. 
Characteristic  is  the  tendency  to  grow  only  in  one  direction  of 
space,  but  occasional  tendency  to  growth  in  two  directions  occurs 
in  the  formation  of  tetrads.  The  chains  also  vary  in  length.  They 
may  be  short,  straight,  or  long  and  curved.  These  characteristics 
depend  upon  the  strain  and  environment. 

Streptococci  grow  best  on  weakly  alkaline  broth,  with  0.2  to 
2  per  cent,  dextrose.  Ordinarily  the  organism  has  no  definite 
capsule,  but  some  especially  virulent  strains  show  capsulation  of 
chains  with  indentation  at  the  point  of  union  of  individuals.  One 


STREPTOCOCCI  17 

of  these  strains,  formerly  spoken  of  as  the  streptococcus  mucosus, 
is  now  classed  with  the  pneumococci,  which  are  intimately  related 
to  the  streptococci.  Very  useful  for  the  differentiation  of  strepto- 
cocci strains  is  cultivation  on  blood  agar  plates  (i  c.c.  defibrinated 
blood  +  6  c.c.  agar).  On  this  medium  some  streptococci  exhibit 
marked  hemolytic  properties.  Each  colony  is  surrounded  by  a  pale 
halo,  hence  the  name  streptococcus  hemolyticus.  Another  strain  pro- 
duces in  similar  manner  a  characteristic  green  pigment  which  encir- 
cles each  colony.  This  is  termed  streptococcus  viridans.  Streptococci 
grow  on  agar  as  grayish  points,  sometimes  as  a  faint  diffuse  layer. 
They  usually  do  not  liquefy  or  peptonize  gelatine,  unless  irregu- 
larly. The  optimum  temperature  of  growth  is  the  usual  one  of 
incubation,  and  the  extreme  limits  are  43°C.  and  12°  to  I5°C.  They 
are  facultative  aerobes  and  grow  well  on  exclusion  of  air.  Some 
streptococci  form  lactic  acid  from  milk  and  coagulate  it,  eventually 
checking  their  growth,  unless  neutralized;  others  only  attack  the 
glucose  in  milk  with  no  clotting.  Cultures  remain  transferable  for 
months,  particularly  those  coming  from  pus  and  erysipelas.  Throat 
and  intestinal  cultures  are  usually  less  resistant.  The  usual  patho- 
genic streptococci  are  Gram  positive.  Gram-negative  streptococci 
are  generally  saprophytes. 

STREPTOCOCCUS  DISEASES 

OF  SKIN  AND  SUBCUTANEOUS  TISSUES.  The  most  important  is 
erysipelas,  a  disease  recognized  since  ancient  times  and  well  known 
to  the  Hippocratic  school  as  epidemic.  Hunter  and  Gregory,  in  the 
eighteenth  century,  recognized  its  contagiousness,  and  Volkmann 
established  the  disease  in  1869  as  a  most  important  wound  infection. 

Erysipelas  is  a  migrating,  sharply  demarcated  inflammation  of 
the  skin,  easily  recognized  by  its  red  color  and  saltatory  progress. 
It  may  be  either  superficial  or  deep,  extending  through  the  rete 
Malpighii  and  deeper.  The  inflammatory  exudate  is  serous,  raising 
blisters,  or  it  may  become  phlegmonous,  purulent,  and  even  gan- 
grenous. In  these  severe  cases  it  may  extend  to  the  mucous  mem- 
branes, the  serous  cavities  or  joints.  The  period  of  incubation 
(time  from  infection  to  outbreak  of  disease)  varies.  In  animals  it 
is  only  15  to  61  hours,  in  man  much  longer,  6  to  14  days,  on  an 
2 


1 8  GENERAL  PATHOLOGY 

average  one  week;  the  duration  is  from  10  to  14  days.  Abortion  of 
an  attack  is  possible. 

Streptococci  are  not  found  in  the  reddened  parts,  but  in  the 
lymphatics  and  tissue  spaces  of  the  periphery  not  in  the  blood 
vessels.  The  reddened  central  parts  contain  a  hemorrhagic  serous 
exudate  within  necrotic  tissue.  This  may  give  way  to  purulent 
infiltration  and  even  abscess  formation.  The  original  .idea  of 
Fehleisen  that  erysipelas  is  excited  by  a  specific  streptococcus  is  no 
longer  entertained,  since  it  is  known  that  streptococci  from  many 
foci,  from  abscesses,  throat  in  scarlet  fever,  tonsillar  affections, 
etc.,  may  be  responsible.  Not  all  persons  are  equally  disposed  to 
the  disease.  The  skin  of  persons  in  certain  trades,  as  blacksmiths, 
bakers  and  cooks,  seems  more  susceptible.  The  same  applies  to  the 
skin  of  blond  individuals,  while  brunettes  are  less  liable  to  infection. 
Individual  idiosyncrasy  towards  the  disease  is  great.  Moreover, 
once  having  occurred  it  is  liable  to  habitual  recurrence  (cocci  doi/ 
not  die,  but  attenuate  and  gain  new  virulence).  Before  the  times 
of  antisepsis  erysipelas  was  a  gravely  feared  disease  of  surgical 
wards  and  hospitals.  Since  the  introduction  of  antisepsis  and 
asepsis  it  has  lost  much  of  its  previous  horror. 

Streptococci  frequently  combine  with  staphylococci  in  abscess 
formation  or  phlegmonous  inflammations  of  the  skin.  In  dirty 
wounds  they  associate  themselves  with  putrefactive  bacteria.  There 
are  numerous  other  skin  lesions  in  which  streptococci  are  found, 
especially  in  impetigo  contagiosa,  also  erythema  multiforme,  scar- 
let fever,  etc.  Here  are  concerned  not  only  the  micro-organisms 
themselves,  but  their  toxines. 

OF  THE  THROAT.  Mucous  membranes,  especially  of  mouth  and 
throat,  are  favorable  places  for  lodgment,  growth  and  penetration 
of  streptococci.  The  same  applies  to  the  lymphoid  tissue  in  these 
situations,  especially  the  tonsils.  Up  to  45  per  cent,  of  healthy 
tonsils  show  the  presence  of  streptococci,  and,  generally  speaking, 
there  exists  a  rich  bacterial  flora  in  the  mouth  and  gastro-intes- 
tinal  tract.  Streptococci  grow  well  in  the  alkaline  secretions  of 
mucous  membranes,  especially  when  the  secretion  is  abundant  and 
contains  many  desquamated  and  necrotic  cells.  Thus  a  catarrhal 
condition  of  mucous  membranes  favors  the  growth  of  streptococci. 


STREPTOCOCCI  19 

Very  important  also  is  any  injury  to  the  mucous  membrane, 
either  by  physical  or  chemical  agents,  or  by  other  bacteria,  such 
as  the  diphtheria  bacillus,  or,  as  it  occurs  in  measles,  typhoid  fever, 
etc.  Here  streptococci  invade  through  the  injured  mucous  mem- 
brane, often  directly  with  the  original  cause  of  the  injury  and  con- 
tribute to  a  mixed  infection.  The  streptococcus  infection  may  then 
even  exceed  the  importance  of  the  primary  infection,  increase  its 
virulence,  or  give  it  a  new  character  (necrosis  of  tissues  and  gen- 
eral septicemia).  Streptococci,  therefore,  are  found  in  practically  all 
inflammations  of  the  throat,  from  the  mildest  to  the  most  severe. 

IN  BRONCHI  AND  LUNGS.  Streptococci  cause  disease  either  alone 
(aspiration  pneumonia,  pyemia)  or,  more  important,  as  secondary 
infection.  In  this  connection  the  relation  to  tuberculosis  deserves 
special  mention.  Koch  himself  showed  as  early  as  1884  the  impor- 
tance of  streptococci  in  the  progress  of  tuberculosis  of  the  lung. 
Streptococci  follow  the  path  of  the  tubercle  bacillus,  may  even 
precede  it,  and  are  largely  responsible  for  the  rapid  fusion  of  tuber- 
culous tissue,  ulceration  and  cavity  formation. 

OF  THE  GASTROINTESTINAL  TRACT.  Here  they  are  as  abundant 
as  in  the  throat.  They  seem  to  have  etiological  relation  to  some  diar- 
rheas, especially  of  children.  They  may  either  enter  through  the  mu- 
cous membrane  or  reach  the  gut  by  way  of  the  lymphatics,  even 
from  remote  foci.  Thus  appendicitis  is  thought  by  some  to  be 
due  to  lymphatic  extension  from  a  tonsilar  focus.  Similar  views 
are  held  as  to  the  origin  of  some  streptococcus  types  of  dysentery. 

OF  BONES  AND  JOINTS.  Streptococci  have  not  the  same  impor 
tance  in  osteomyelitis  that  staphylococci  have,  but  their  affinity 
is  greater  for  joints.  They  are  responsible  for  purulent  synovitis 
and  arthritis  as  parts  of  a  general  pyemic  process,  and  also  seem 
to  settle  in  joints  as  the  primary  focus  of  infection.  Some  investiga- 
tors hold  that  certain  specific  strains  of  streptococci  are  responsible 
for  acute  articular  rheumatism  and  that  this  disease,  with  its  fre- 
quent accompanying  endocarditis,  is  to  be  regarded  as  a  strepto- 
coccus pyemia. 

IN  PUERPERIUM.  Very  important  are  the  puerperal  infections 
with  streptococci.  They  take  their  origin  from  the  wounds  and 
injuries  of  the  uterus  during  or  after  confinement.  That  puerperal 


20  GENERAL  PATHOLOGY 

fever  was  of  contagious,  transmitted  origin  was  suspected  by  Oliver 
Wendell  Holmes  in  1843,  but  a  substantial  support  of  this  idea 
was  not  furnished  until  Semmelweiss  showed,  in  1861,  that  the 
puerperal  mortality  could  be  greatly  reduced  by  cleanliness  and 
care  of  operator  and  instruments.  His  observations,  however,  were 
scorned  and  disregarded.  Actual  proof  of  Semmelweiss'  contention 
came  with  the  advent  of  bacteriology.  The  typical,  pronounced  infec- 
tion is  a  purulent  gangrenous  inflammation  of  the  mucous  mem- 
brane of  the  uterus  (septic  endometritis).  It  may  penetrate  to  the 
musculature  of  the  uterus  and  the  surrounding  connective  tissue 
(septic  metritis  and  parametritis).  Infective  thrombi  are  formed 
in  the  large,  exposed  blood  channels  and  lymphatics  of  the  uterus 
and  in  the  parametrium.  Extension  of  the  parametritis  leads  to 
peritonitis  and  through  lymph  and  blood  stream  to  pleuritis, 
pericarditis  and  mediastinitis. 

By  entrance  of  micro-organisms  into  large  veins  (vena  spermat- 
ica  interna),  opportunity  for  a  general  pyemia  is  given.  In  no 
other  infection  does  the  streptococcus  possess  greater  importance 
or  greater  virulence,  and  nowhere  are  the  anatomical  conditions 
more  favorable  for  its  location  (necrotic  tissue)  and  invasion  (large 
bleeding  surfaces).  Severe  complications  with  other,  especially  pu- 
trefactive bacteria,  increase  the  danger.  Streptococci  are  conveyed 
to  the  exposed,  susceptible  parts,  in  at  least  the  majority  of  cases, 
from  the  outside  by  hands,  instruments,  bandages,  tampons,  etc. 

The  question  of  autoinfection  by  streptococci  normally  present 
in  the  vagina  has  also  been  raised.  While  this  possibility  cannot  be 
absolutely  denied,  it  is  certainly  not  as  important  a  source  of 
infection  as  introduction  from  outside,  and  only  possible  under 
unusual  circumstances.  It  is  true  that  streptococci  occur  in  the 
vagina,  but,  as  the  observations  of  Doderlein  and  others  showed, 
these  are  rendered  innocuous  by  the  strongly  acid  secretion  of 
the  vagina.  Only  the  pathological  secretion  in  catarrh,  especially 
in  gonnorhea,  becomes  weakly  acid  or  alkaline.  In  these  reactions 
mucus  would  be  a  good  culture  medium.  Under  such  conditions 
the  development  and  increase  in  virulence  of  vaginal  streptococci 
is  conceivable,  but  not  proved.1 

1  Von  Herff  figures  for  10,000  labors  one  hematogenous  puerperal  infection, 
that  is,  not  caused  by  local  infection. 


STREPTOCOCCI  21 

SEPTICEMIA  AND  PYEMIA.  Reference  has  already  been  made  sev- 
eral times  to  generalization  of  streptococci  throughout  the  body. 
Such  a  condition  is  known  as  septicemia  or  bacteriemia.  The 
latter  name  is  now  preferred  by  some  as  being  more  definite.  When 
under  such  conditions  local  manifestations  are  added,  as  joint 
lesions,  multiple  abscesses,  inflammation  of  serious  membranes,  etc., 
the  process  is  termed  pyemia.  Entrance  of  the  micro-organisms 
may  occur  either  directly  or  indirectly  through  the  lymph  cir- 
culation (lymphangitis).  When  only  small  numbers  are  thus 
swept  into  the  blood  stream,  they  are  usually  made  innocuous 
by  the  antibacterial  properties  of  the  blood.  In  large  numbers, 
however,  they  overgrow  the  body,  or  as  already  stated,  locate 
in  parts,  either  through  mechanical  arrest  or  through  special 
anchoring  affinities  of  certain  tissues  (receptors,  chemical  and 
biological  relation  of  tissues  to  invading  organism — see  page  108). 

In  general  infections  blood  culture  shows  the  presence  of  strepto- 
cocci. This  may  be  taken  as  indication  of  the  inability  of  the  host 
to  fix  and  destroy  bacteria  locally.  In  withdrawing  blood  for  culti- 
vation in  broth,  conveniently  from  a  larger,  peripheral  vein  of  the 
arm,  5  to  10-20  c.c.  are  taken  and  ^volume  of  a  2  per  cent,  solution 
of  sodium  citrate  added  to  prevent  coagulation  and  bactericidal 
action.  Otherwise  a  small  volume  of  blood  must  be  diluted  with  a 
relatively  large  amount  of  broth  (several  hundred  c.c.)  in  order  to 
avoid  any  bactericidal  action  of  the  blood  serum,  whereby  growth 
is  inhibited.  General  streptococcus  infections  present  the  picture  of 
an  intoxication  with  remittant,  so-called  septic  temperature. 

SPECIFICITY  OF  STREPTOCOCCUS  DISEASES.  Originally,  under  the 
influence  of  early  bacteriological  teaching,  it  was  held  that  every 
disease  had  its  specific  micro-organisms  and  that  these  were  fixed 
in  type  and  pathogenicity.  It  has  already  been  mentioned  that 
Fehleisen  considered  his  so-called  streptococcus  erysipelatos  entirely 
distinct  from  others.  It  was  found,  however,  that  one  type  may 
cause  erysipelas,  phlegmon  and  general  sepsis,  even  in  the  same 
host,  and  that  these  various  manifestations  of  streptococcic  in- 
fections depend  upon  certain  variable  factors  in  the  streptococci 
strains  and  in  the  host.  These  variables,  which,  it  may  be  added, 
apply  not  only  to  streptococcus  infections,  but  to  infections  with 


22  GENERAL  PATHOLOGY 

other  micro-organisms  as  well,  determine  occurrence,  location  and 
character  of  the  disease  and  may,  therefore,  be  spoken  of  as  "rela- 
tive determinants."  Recent  investigations  have  further  confirmed 
these  views  and  have  especially  emphasized  the  great  variability 
in  cultural  characteristics  and  virulence  of  streptococci  strains  as 
influenced  by  their  source  and  previous  history. 

The  following  table  summarizes  the  factors  entering  into  the 
formation  of  relative  determinants: 

TABLE  I 

FACTORS    DETERMINING    CHARACTER    AND,  VIRULENCE    OF    STREPTOCOCCUS 

INFECTION 

(Relative  Determinants) 

A.  In  the  Streptococcus.  Fluctuations  and  variations  in  type.  These  depend 

upon 

(1)  Source  (Animal,  etc.).  Virulence  increased  by  successive  passage 
through  animals  of  the  same  type. 

(2)  Soil,  (a)  Quantitative:  nutrition  of  host,  good:  virulence,  plus. 

nutrition  of  host,  bad:  virulence,  minus. 

(6)  Qualitative:  affinity  for  tissues  previously  inhabited  (re- 
ceptors) such  as  joints,  skin,  etc. 

B.  In  the  Host: 

(1)  Local  Determinants,  (a)  Anatomical  structure  (mechanical  arrest 

by  capillary  loops  in  kidney  glomeruli,  or 
in  spleen,  etc.). 

(6)  Pathological  lesions:  blocking  of  paths  of 
travel  by  exudate,  etc. 

(2)  General  Determinants,  (a)  Antibactericidal  action  (a)  general. 

(|8)  specific  as  re- 
sponse to  a 
particular 
invasion. 

(6)  Individual  organization  (a)  age  period, 

(as  suscep- 
tibility    t  o 
bone    infec- 
t  i  o  n      in 
youth,  etc.) 
(/3)  s  p  e  c  i  fi  c, 
gro  uped 
collective- 
ly  as   dis- 
position. 


BACILLUS  PYOCYANEUS  23 

This  table  explains  the  possibility  of  a  large  number  of  easily 
variable  and  fluctuating  streptococcus  strains,  both  pathogenic 
and  saphrophytic.  This  is  borne  out  by  facts.  Even  saphrophytic 
strains  may  thus  acquire  pathogenic  properties  and  mild  or  severe 
virulence. 

An  attempt  has  been  made  of  late  to  classify  and  differentiate  the 
various  streptococcus  strains  by  their  behavior  towards  various 
sugars,  but  this  is  still  in  the  experimental  stage.  Another  method  of 
streptococcus  classification  is  that  of  Avery,  and  depends  upon 
their  acid  production.  The  acid  production  differs  apparently  in 
bovine,  human  and  saprophytic  strains.  Thus  milk  streptococci 
produce  more  acid  than  those  from  the  throat.  While  of  interest, 
this  method  is  at  present  not  sufficiently  advanced  to  allow  a 
classification  for  pathological  use. 

Recently  it  has  been  claimed  by  Rosenow  that  streptococci  may 
be  "trained"  to  the  production  of  specific  diseases,  for  instance 
for  gastric  ulcer,  and  that  this  property  once  acquired  remains 
fixed  in  the  strain.  Substantiation  of  this  assertion  by  others  has 
not  been  forthcoming  and,  when  it  is  considered  upon  how  many 
different  and  variable  factors  a  disease  depends  besides  the  in- 
fecting agent,  this  claim  requires  confirmation  before  it  can  be 
entertained. 

BACILLUS  PYOCYANEUS.  This  organism,  which  produces,  as  its 
name  implies,  blue  or  green  pus,  is  conveniently  considered  as  an 
appendix  to  the  foregoing  pus  producer,  although  it  is  not  a  coccus, 
but  a  rod.  It  was  of  much  greater  importance  in  the  days  before 
antisepsis  and  asepsis,  for  it  was  quite  common  to  observe  it  in 
suppurating  wounds  with  bluish  or  greenish  pus.  The  cause  of 
this  peculiar  pigment  was  discovered  in  1882  by  Gessard  in  a  pig- 
ment-producing bacillus. 

This  organism  is  a  short  rod,  I  to  2ju  in  length,  small,  slender, 
actively  motile  and  does  not  form  spores.  It  stains  easily  with  the 
ordinary  dyes,  but  is  negative  to  Gram.  In  culture  it  is  a  faculta- 
tive anaerobe,  but  its  pigment  is  produced  only  in  the  presence  of 
oxygen.  It  grows  well  on  practically  all  media  in  acid  or  alkaline 
reaction  in  the  form  of  an  abundant,  grayish  glistening  layer  on 
the  surface  of  the  solid  medium  and  produces  pigment  in  about  a 


24  GENERAL  PATHOLOGY 

day.  On  broth  it  also  grows  on  the  surface  as  a  thick  pellicle.  It 
coagulates  milk.  The  pigment  is  called  pyocyanin,  and  is  originally 
a  colorless  base  which  becomes  green  or  blue  only  on  exposure  to 
oxygen.  Some  strains  produce  a  fluorescent  pigment.  The  organism 
by  itself  possesses  only  mild  pathogenic  properties  and  often  lives 
only  as  a  harmless  saprophyte  on  the  skin  or  in  the  gut.  It  exhibits 
pathogenic  properties  only  in  feeble,  reduced  and  senile  individuals 
and  in  infants.  In  unclean  wounds  it  is  often  a  secondary  invader 
with  other  pus-producing  organisms,  such  as  staphylococci  and 
streptococci,  giving  the  pus  a  faint  to  deep  bluish  or  greenish  color. 


CHAPTER  III 
DIPLOCOCCUS  PNEUMONIA 

THE  DIPLOCOCCUS  PNEUMONIA.  This  organism,  closely  related 
to  the  streptococci,  is,  as  the  name  implies,  the  most  frequent 
cause  of  pneumonia.  The  disease  was  originally  considered  the 
result  of  cold  and  prolonged  chilling  of  the  body,  which  were  sup- 
posed to  drive  and  congest  the  blood  into  the  internal  organs 
and  especially  the  lungs.  But  Skoda  and  Jiirgensen  were  al- 
ready convinced  of  the  infectious  nature  of  the  disease.  After 
several  investigators  had  found  the  presence  of  cocci  in  the  sputum 
and  exudate  of  pneumonic  patients,  Frankel  and  Weichselbaum 
independently  identified  this  capsulated  diplococcus  as  an  almost 
constant  concomitant  of  pneumonia,  and  further  found  that  the 
organism  cultured  from  human  sputum  and  injected  into  animals 
caused  septicemia. 

While  the  pneumonoccus  is  found  in  perhaps  the  majority  of 
cases  of  straightforward  pneumonia,  it  must  be  emphasized  that 
it  is  by  no  means  the  only  cause.  Other  organisms  may  also  be  con- 
cerned, such  as  ordinary  streptococci,  staphylococci,  the  influenza 
bacillus,  the  typhoid  bacillus,  the  diphtheria  bacillus  and  others. 
Inflammation  of  the  lung  does  not,  therefore,  differ  in  this  respect 
from  other  inflammations.  It  may  be  caused  by  a  variety  of  organ- 
isms. On  the  other  hand  the  pathogenic  effects  of  the  diplococcus 
pneumoniae  are  by  no  means  entirely  confined  to  the  lung.  On  the 
contrary  it  may  be  responsible  for  inflammations  elsewhere,  in 
the  meninges,  middle  ear,  peritoneum,  etc.  These  may  either  follow 
a  pneumonia  or  may  occur  without  it.  In  other  words  while  the 
diplococcus  pneumoniae  possesses  a  special  affinity  for  anchorage 
in  the  lungs,  this  property  is  not  exclusive  and  illustrates,  as  in 
other  organisms,  lack  of  absolute  etiological  specificity. 

The  pneumococcus  presents  in  recent  state  a  typical  mor- 
phology. It  is  somewhat  elongated,  lancet-shaped,  in  pairs,  hence 

25 


26  GENERAL  PATHOLOGY 

called  diplococcus  lanceolatus.  It  is  occasionally  arranged  in  short 
chains  which  always  display  close  union  of  two  (diploid)  organisms. 
Characteristic  is  its  distinct  capsule,  a  clear  halo  which  surrounds 
either  one,  frequently  two  organisms.  If  short  chains  are  found, 
which  is  common  in  the  type  of  pneumococcus  formerly  spoken 
of  as  the  streptococcus  mucosus,  the  capsule  is  indented  at  the 
point  of  junction  of  pairs.  The  capsule  disappears  usually  on 
artificial  cultivation  and  is  regarded  as  an  indication  of  strong 
virulence.  It  is  retained  only  under  very  favorable  conditions  of 
cultivation  (in  fluid  sera  and  non-coagulated  albuminous  fluids). 
Cultures  ferment  inulin  with  the  production  of  acid,  which  is  a 
distinguishing  reaction  from  streptococci.  (Streptococcus  mucosus 
ferments  inulin,  putting  it  into  the  pneumococcus  class.)  The 
pneumococcus  dies  rapidly  on  culture,  being  an  obligatory  para- 
site. Its  death  is  hastened  by  strong  acid  formation.  Frequent 
transplants  are,  therefore,  necessary  to  keep  it  going  even  for  a 
short  time.  These  may  fail.  In  sputum  and  blood  the  virulence  is 
maintained  longer. 

The  recent  observations,  especially  of  Dochez  and  other  workers 
at  the  Rockefeller  Institute  in  New  York,  have  shown  that  the 
pneumococcus  occurs  in  a  number  of  strains.  Of  these  four  may 
be  recognized  as  distinct  in  certain  cultural  characteristics  and 
virulence.  The  first  two  are  the  common,  typical  pneumococcus 
forms;  the  third  is  the  organism  spoken  of  as  streptococcus  muco- 
sus; the  fourth  is  a  relatively  virulent  form  which  is  common  in 
the  mouths  of  healthy  persons.  Of  these  four  forms,  the  third  is  the 
most  virulent;  then  comes  Nos.  i  and  2,  and  finally  No.  4.  Mix- 
tures of  these  are  not  infrequently  encountered  in  infections. 

Besides  in  the  mouth  pneumococci  occur  on  other  normal 
mucous  membranes,  such  as  those  of  the  nose,  throat,  pharynx 
and  conjunctiva,  apparently  waiting  for  an  opportunity  to  invade. 

The  investigations  of  Weichselbaum  demonstrated  this  organism 
in  94  cases  of  129  pneumonias.  The  diplococcus  pneumoniae  is 
most  abundant  at  the  beginning  of  the  inflammation  in  the  lung 
and  in  the  earliest  inflammatory  areas.  In  older  or  healing  lesions 
they  become  scarcer,  lose  the  capsule  and  disappear.  They  are 
seen  in  the  alveoli,  lymph  and  blood  vessels,  free  or  in  leucocytes. 


DIPLOCOCCUS  PNEUMONIA  27 

They  travel  by  means  of  the  lymphatics  to  the  pleura  and  to  the 
glands  at  the  hilus  of  the  lung,  enter  the  general  circulation  and 
disseminate  through  the  rest  of  the  body  as  pneumococcus  septi- 
cemia.  Pneumonia  should,  therefore,  be  regarded  not  simply  as 
an  inflammation  of  the  lung,  but  rather  as  a  septicemia  or  bacteri- 
emia,  with  local  manifestations  in  the  lung.  This  explains  the  other, 
frequent  complications  in  the  disease.  The  occurrence  of  the  dip- 
lococcus  in  pneumonic  sputum  is  constant. 

Mixed  infection  with  other  micro-organisms  is,  on  the  whole,  rare, 
but  may  occur  with  bacillus  influenzse,  streptococci  and  staphy- 
lococci,  rarer  with  putrefactive  bacteria  in  unresolved  and  stagnant 
inflammatory  exudates.  Broncho-pneumonia  may  be  excited  by 
this  diplococcus,  but  is  more  frequently  due  to  other  organisms. 
Complications  of  pneumonia,  such  as  pleuritis,  pericarditis,  menin- 
gitis, etc.,  are  the  results  of  lymphatic  extension  and  generalization 
of  the  infection.  But  pneumococcus  pleuritis,  peritonitis  and  menin- 
gitis may  occur  without  any  involvement  of  the  lungs.  In  primary 
pneumococcus  meningitis  the  organism  enters  probably  directly 
from  the  accessory  cavities  of  the  nose  or  middle  ear.  Rarer  pneu- 
mococcus diseases  are  arthritis,  periarthritis  and  pyemia. 

The  pneumococcus  produces  a  characteristic  thick,  creamy  pus, 
slightly  greenish,  but  clear,  which  compares  with  the  dirty,  serous, 
hemorrhagic  exudate  in  streptococcus  infections. 

In  animals  the  pneumococcus  does  not,  under  ordinary  circum- 
stances, cause  pneumonia,  but  a  septicemia  only.  Wadsworth,  how- 
ever, has  succeeded  in  inducing  in  rabbits  pulmonary  lesions  by 
direct  intratracheal  introduction,  after  partial  immunization 
against  the  diplococcus  through  previous  attenuated  small  doses 
of  the  organism.  This  may  have  enabled  the  animals  to  fix  or  an- 
chor the  pneumococcus  in  the  lungs. 


CHAPTER  IV 

DIPLOCOCCUS     INTRACELLULARIS     MENINGITIDIS, 
GONOCOCCUS  AND  MICROCOCCUS  CATARRHALIS 

DIPLOCOCCUS  INTRACELLULARIS  MENINGITIDIS.  Also  known 
as  meningococcus.  This  organism  is  the  cause  of  epidemic  cerebro- 
spinal  meningitis.  Next  to  the  pneumococcus  and  tubercle  bacillus 
it  is  the  chief  etiological  factor  in  this  disease. 

After  Klebs,  Eberth,  Marchiafava  and  Celli  had  observed  cocci 
in  the  exudate  of  epidemic  cerebrospinal  meningitis,  Weichselbaum, 
in  1887,  described  as  the  diplococcus  intracellularis  meningitidis, 
an  organism  distinct  from  the  pneumococcus,  and  this  finding 
was  later  confirmed  by  others.  Morphologically  this  organism  is 
similar  to  the  gonococcus  (see  later).  It  appears  in  pairs  or  tetrads, 
even  in  groups,  and  has  a  great  tendency  to  lie  in  leucocytes, 
hence  "intracellularis."  It  divides  in  two  planes,  so  that  the  name 
micrococcus  is  preferred  by  some.  It  is  non-motile  and  forms  no 
spores.  An  important  difference  from  many  other  pathogenic  cocci 
is  its  Gram-negative  character,  which  it  shares  with  the  gonococcus 
and  the  micrococcus  catarrhalis  of  Pfeiffer. 

In  culture  it  grows  only  feebly  at  temperatures  from  37°  to 
42°C.  On  agar  plates  grayish  colonies  2  mm.  in  diameter,  with 
smooth,  slightly  elevated  edges  appear  in  24  hours.  These,  on  mag- 
nification, are  finely  granular.  On  blood  and  serum  agar  growth  is 
more  luxuriant,  so  that  in  24  hours  colonies  of  about  3  to  4  mm. 
in  diameter  appear.  The  addition  of  i  per  cent,  dextrose  seems  to 
favor  growth.  On  slanted  agar  growth  is  uncertain  and  poor.  In 
broth  slight  turbidity  is  produced.  It  grows  in  milk  without  coagu- 
lation. It  does  not  ferment  to  acid  mannose,  saccharose  and  levu- 
lose,  but  only  dextrose  and  maltose.  Neutral  reaction  is  most 
favorable. 

The  meningococcus  is  essentially  an  aerobe,  and  does  not  grow 
on  exclusion  of  air.  Frequent  transfers  (from  2  to  3  days)  in  culture 
are  necessary  to  have  it  retain  its  viability.  It  is  a  strict  parasite, 
and  dies  easily  on  culture  media,  and  when  exposed  to  drying 

28 


GONOCOCCUS  29 

(in  about  24  hours).  Its  pathogenicity  to  animals  is  low.  White 
mice  are  more  susceptible  than  other  animals,  but  even  subcuta- 
neous injection  is  tolerated  by  them.  Subdural  introduction  into 
monkeys  is  followed  by  meningitis. 

The  organism  is  a  constant  finding  in  epidemic  meningitis.  It 
produces  a  fibrinous  or  sero-fibrinous  inflammation  of  the  pia 
arachnoid  which  not  infrequently  extends  to  the  cerebral  substance. 
The  number  of  cocci  in  the  inflammatory  exudate  varies.  They  are 
usually  scarce  and  lie  mostly  in  leucocytes.  The  path  of  entrance 
to  the  brain  is  not  quite  clear.  It  is  held  that  this  is  probably 
through  the  nose  and  accessory  skull  cavities  (Flexner)  where  the 
micrococcus  meningitidis  has  been  found  in  healthy  subjects,  who 
may  act  as  carriers  of  the  disease.1  These  findings  have  not  always 
been  beyond  all  doubt,  because  of  the  possibility  of  confusing  the 
meningococcus  with  the  micrococcus  catarrhalis  of  Pfeiffer,  with 
which  it  has  some  similarity  (see  later). 

General  dissemination  through  the  body,  that  is,  a  septicemia, 
seems  to  be  rare.  The  diagnosis  can  usually  be  made  during  life  of 
the  patient  by  spinal  lumbar  puncture  and  withdrawal  of  some  of 
the  exudate  for  microscopic  examination  and  culture. 

GONOCOCCUS. — The  venereal,  purulent  inflammation  of  the  ure- 
thra can  be  traced  with  certainty,  much  better  than  syphilis,  to  the 
remotest  periods  of  antiquity.  The  works  of  the  ancient  physi- 
cians give  ample  proof  that  the  disease  was  generally  recognized 
very  early  amongst  peoples  of  all  cultures.  Even  its  infectious 
character  and  contagiousness  by  contact  had  been  fully  recognized 
and  during  the  Middle  Ages  efforts  were  made  to  prevent  its 
spread  by  police  regulations,  such  as  examination  of  prostitutes, 
etc. 

But  during  the  last  part  of  the  fifteenth  century  (about  1490) 
there  occurred  that  remarkable  epidemic  of  syphilis  which  obscured 
and  even  lost  everything  that  had  been  recognized  of  gonorrhea  as 
an  affection  sui  generis.  During  this  period  there  occurred  a  number 
of  extraordinary  events  of  most  unfortunate  consequences  for  the 
whole  of  Europe,  and  these  made  possible  a  marvelous  epidemic 

1  Embleton  has  recently  shown  that  these  cocci  may  be  carried  deep  into  the 
mucous  membrane  so  that  their  detection  may  be  missed  in  superficial  swabs. 


30  GENERAL  PATHOLOGY 

and  spread  of  another  veneral  disease,  syphilis,  throughout  the 
western  hemisphere.  All  attention  became  centered  upon  it  and 
all  other  venereal  diseases  were  disregarded,  or  identified  with  it. 

For  several  years  bad  seasons  in  Italy,  France  and  Germany  had 
brought  poor  harvests  and  famine.  Other  epidemics,  plague, 
typhus,  etc.,  overran  the  south  and  west  of  Europe.  Social  con- 
ditions were  at  lowest  ebb,  but  the  corruption  of  morals  amongst 
both  sexes  had  reached  an  extraordinary  height.  Added  to  these  came 
the  turmoil  of  war.  The  army  of  licentious,  lawless  bands  of  Charles 
VIII  returning  from  Italy  overran  France,  Switzerland,  Germany 
and  the  Netherlands.  They  carried  with  them,  according  to  cred- 
itable contemporary  writers,  the  germs  of  syphilis  ("Morbus 
gallicus,  the  French  pocks").  Thus  the  disease  spread  rapidly  from 
Southwest  to  North  and  East,  carried  by  loafers,  unscrupulous 
gentry  and  even  the  better  classes. 

Under  the  impression  of  this  venereal  epidemic,  all  other  vener- 
eal diseases  were  regarded  as  manifestations  of  it.  The  identity  of 
syphilis  and  gonorrhea  was  established  and  remained.  As  great  a 
man  as  John  Hunter  still  supported  it  and  endeavored  to  prove 
it  by  self-sacrificing  self-inoculation.  It  was  Ricord's  merit  (1832) 
to  succeed  in  establishing  once  more  gonorrhea  as  distinct  from 
syphilis,  but  while  he  regarded  it  as  an  independent  infection,  he 
did  not  recognize  it  as  a  specific  disease,  but  as  a  simple  catarrh 
of  the  urethral  mucous  membrane,  excited  only  by  a  non-specific 
irritation  of  the  vaginal  secretion.  Further  investigation  by  others 
soon  showed  the  fallacy  of  this  conception,  for  it  was  impossible 
to  produce  typical  gonorrhea  with  ordinary  pus. 

Finally,  in  1879  Neisser  succeeded  in  discovering  the  specific 
cause  of  the  disease.  He  described  the  organism  as  a  diplococcus 
of  biscuit  form  and  situated  with  preference  in  leucocytes.  For  a 
time  the  organism  withstood  attempts  at  cultivation.  Bumm  finally 
succeeded  in  this  difficult  task  by  employing  human  blood  serum 
as  medium.  He  also  proved  its  infectiousness  by  direct  inoculation 
on  the  human  urethra. 

The  coccus  is  about  i.6ju  in  size,  or  less,  0.8  to  o.6/z.  Cocci  lie  in 
the  pus  cell  body  (usually  polymorphonuclear  and  plasma  cells) 
sometimes  in  great  numbers.  It  appears  that  in  the  acute  stage 


GONOCOCCUS  31 

the  cocci  are  mostly  intracellular.  In  the  chronic,  they  are  more  apt 
to  lie  outside  of  cells.  But  this  behavior  is  only  to  be  observed  in  the 
exudate  on  the  surface  of  the  urethral  mucous  membrane,  not 
in  the  tissues.  This  phenonemon,  known  as  phagocytosis,  repre- 
sents active  cell  action  and  not  an  invasion  by  the  gonococci,  for 
they  are  taken  up  rapidly  by  leucocytes  on  artificial  media  and  the 
organisms  themselves  are  non-motile. 

The  gonococcus  stains  with  ordinary  dyes,  but  is  Gram  negative. 
It  is  extremely  difficult  to  cultivate,  and  grows  only  in  the  presence 
of  uncoagulated  protein,  i.e.,  human  serum.  No  growth  takes  place 
on  broth  or  gelatine.  A  successful  culture  medium  is  the  agar  serum 
of  We'rtheim,  which  consists  of  2  to  3  parts  broth  peptone  agar  and 
i  part  serum  or  pleuritic,  cystic  or  serous  fluid.  The  cultured  or- 
ganisms have  been  found  to  reproduce  the  disease  in  human  beings. 

The  temperature  limits  are  30°  to  38°C.,  the  optimum  37°C. 
The  colonies  appear  in  16  to  20  hours,  and  in  24  hours  are  of  pin- 
head  size,  light  grayish,  mucoid,  tenacious.  In  ascetic  fluid  broth 
only  superficial  growth  occurs,  no  turbidity.  The  organism  is  a 
strict  parasite;  it  succumbs  easily,  even  in  culture,  after  a  few  days. 
Transplantation  is  difficult.  Towards  outside  agents  it  is  very 
susceptible,  especially  to  silver  salts.  These  are,  therefore,  best 
suited  for  treatment. 

The  gonococcus  is  almost  entirely  pathogenic  for  man.  Although 
local  inflammations  and  reactions  have  been  occasionally  produced 
by  endotoxic  action  of  the  bacterial  bodies  in  animals,  there  is 
never  any  growth.  While  the  urethral  mucous  membrane  seems 
most  susceptible,  others  are  open  to  infection,  especially  that  of  the 
conjunctiva  (gonorrheal  ophthalmia),  vagina,  cervix,  uterus  and 
tubes.  The  bladder  is  somewhat  less  susceptible. 

Infection  occurs  by  direct  contact,  as  the  organism  is  strictly 
parasitic.  The  gonococcus  grows  principally  on  the  surface  of  the 
mucous  membranes  and  between  the  epithelial  layers,  but  also 
penetrates  into  the  deeper  tissues  and  extends  by  continuity  to 
adjoining  structures,  Cowper's  glands,  prostate,  epididymis.  Its 
growth  leads  to  an  edematous  imbibition  of  the  mucous  membrane, 
quickly  associated  with  a  marked  purulent  exudate  on  the  surface. 
The  lining  epithelium  is  loosened,  desquamated  and  lost.  The  sub- 


32  GENERAL  PATHOLOGY 

mucous  tissue  appears  infiltrated  with  leucocytes  and  lymphocytes 
(plasma  cells).  As  the  infection  and  inflammation  become  attenuated 
the  lining  cylindrical  epithelium  regenerates,  but  flattens,  and  the 
gonococci  continue  to  grow  around  the  glands  and  in  the  crypts. 
Thus  chronicity  is  established.  It  is  most  important  to  remember, 
however,  that  the  organism  retains  its  virulence  and  that  the  body 
does  not  acquire  protection  against  it.  The  attenuation  of  the 
affection  and  the  decline  in  the  disease  are,  therefore,  not  due  to 
any  real  immunity,  but  rather  to  the  local  changes  in  the  mucous 
membrane  and  the  gradual  adaptation  of  the  mucous  membrane 
and  a  particular  gonococcus  strain  to  each  other.  For  if  these 
chronic  cases  are  revaccinated  with  another  type,  a  superinfection 
results  which  generally  is  milder.  It  is  possible  that  the  local  ana- 
tomical changes  may  be  of  some  mechanical  importance,  as  the 
gonococci  can  no  longer  adhere  so  readily  to  the  altered  surface 
of  the  mucous  membrane.1 

It  is  important  to  appreciate  that  chronic  gonorrhea  is  as  infect- 
ive and  virulent  as  the  acute,  so  that  a  husband  with  chronic 
gonorrhea  may  infect  his  wife  and  then  may  himself  in  time  be 
reinfected  by  his  wife.  The  time  limit  of  infectiousness  in  gonorrhea 
is  difficult  to  determine,  but  it  may  extend  for  years,  especially 
in  women.  Gonococci  disappears  from  the  urethral  secretion  in 
man  after  about  a  year,  but  even  then  infection  cannot  be  ex- 
cluded, as  cultivation  is  so  difficult  (Elser).  MacKenzie  gives 
about  three  years  as  the  probable  time  limit  in  men. 

While  gonorrheal  infections  are  more  frequently  local  and  only 
spread  to  neighboring  glands  (buboes),  general  infection  (septi- 
cemia,  endocarditis)  may  follow.  This  occurs,  according  to  Neisser, 
in  about  0.7  per  cent,  of  cases.  Other  lesions,  such  as  neuritis,  are 
still  rarer.  Somewhat  more  frequent  is  monoarticular  arthritis. 

The  importance  of  gonorrhea  lies  in  its  great  frequency  and  dis- 
tribution as  well  as  its  general  neglect.  Women  particularly  suffer 
in  more  ways  from  the  consequences  than  men.  According  to  Erb 
about  50  per  cent,  of  a  population  suffer  at  one  time  or  an  other 
from  the  disease.  It  is  most  frequently  contracted  in  early  life. 

1  What  has  been  reported  of  antibody  formation  and  successful  vaccine 
treatment  with  attenuated  organisms  is  very  uncertain. 


MICROCOCCUS  CATARRHALIS  33 

Amongst  386  infected  husbands,  85  had  acquired  the  disease 
before  the  twenty-fifth  year.  A  direct  estimate  of  the  number  of 
cases  in  a  community  is  difficult,  as  many  cases  are,  of  course,  never 
reported.  In  armies  and  various  professions  the  figures  vary  from 
1.5  to  3  per  cent,  and  even  much  higher,  10  to  20  per  cent. 

MICROCOCCUS  CATARRHALIS  (PJeiffer).  This  diplococcus,  which 
morphologically  and  in  staining  qualities  resembles  the  meningo- 
coccus  and  gonococcus,  was  isolated  by  Pfeiffer  in  certain  catarrhal 
inflammations  of  the  respiratory  tract,  hence  the  name. 

It  is  Gram  negative  and  grows,  as  contrasted  to  the  gonococcus, 
easily  on  the  common  media.  It  differs  from  the  meningococcus  by 
a  heavier  and  coarser  growth.  It  develops  at  a  temperature  below 
2O°C,  while  the  micrococcus  meningitidis  does  not  below  25°C. 
The  meningococcus  produces  acid  in  milk  without  coagulation. 
The  micrococcus  catarrhalis  leaves  the  reaction  of  milk  unchanged 
or  produces  slight  alkalinity. 

The  following  are  the  chief  points  of  difference  between  gono- 
coccus, meningococcus  and  micrococcus  catarrhalis: 

Gonococcus  grows  poorly  or  not  at  all  on  Loftier 's  blood  serum, 
the  meningococcus  somewhat  better  and  the  micrococcus  catar- 
rhalis even  upon  plain  agar. 

Meningococcus  produces  acid  in  dextrose  and  maltose,  the 
gonococcus  only  in  dextrose,  and  micrococcus  catarrhalis  no  acid 
in  dextrose  or  maltose. 


CHAPTER  V 
BACILLUS  COLI  COMMUNIS 

BACILLUS  COLI  COMMUNIS.  This  bacillus,  the  most  representa- 
tive of  the  so-called  colon  group,  is  perhaps  the  most  important 
member  of  the  intestinal  flora.  The  importance  of  the  intestinal 
flora  was  recognized  after  Pasteur  had  demonstrated  bacterial 
relation  to  fermentation  and  putrefaction. 

Since  Koch's  discoveries  it  became  possible  to  separate,  identify 
and  study  the  intestinal  bacteria.  Bienstock  was  the  first  to  attempt 
to  trace  intestinal  decomposition  to  bacterial  activity.  It  is  curious 
that  he  missed  the  discovery  of  this,  the  most  important,  inhabi- 
tant of  the  intestinal  tract.  It  was  reserved  for  Escherich  ( 1 886)  to 
recognize  it  in  the  stools  of  breast-fed  children,  together  with  the 
bacterium  lactis  aerogenes  and  other,  more  or  less  inconstant, 
bacterial  forms.  He  found  the  bacterium  coli  in  increasing  quantity 
towards  the  lower  parts  of  the  gut,  while  the  bacterium  lactis 
aerogenes  inhabited  the  small  intestines.  This  organism  is  a  greater 
gas  former  than  the  bacillus  coli,  fermenting  sugars  into  CO2  and  H. 

These  investigations  of  Escherich  established  the  regular  occur- 
rence .of  bacillus  coli  in  the  gut  and  also,  as  in  the  bacteria  lactis, 
the  relationship  of  certain  intestinal  organisms  to  decomposition 
of  foodstuffs.  Further  investigations  demonstrated  that  the  bacil- 
lus coli  is  not  an  absolutely  fixed  type,  but  rather  a  group,  variable 
within  certain  limits,  in  which  the  members  differ  from  each  other 
in  culture  and  pathogenicity. 

In  a  broad  sense  the  colon  group  comprises  the  colon  members,  the 
typhoid  bacillus  and  the  various  types  of  so-called  paratyphoid 
bacilli.  Of  the  colon  members  there  are  two  common  forms  which 
may  serve  as  a  basis  for  descriptions;  the  bacillus  coli  communis 
and  the  bacillus  coli  communior,  differing  only  in  very  slight 
cultural  points  (acid  and  gas  production  from  saccharose).  The 
latter  is  more  common  in  the  gut,  hence  the  name. 

34 


BACILLUS  COLI  COMMUNIS  35 

The  colon  bacillus  is  a  plump,  straight  rod  with  rounded  edges. 
The  length  exceeds  the  breadth  by  three  to  four  times.  The  average 
length  is  1-5/4  or  2-4/*,  the  breadth  0.4-0.71*. 

Some  individuals  display  bright,  refractive  polar  bodies  or  pseudo- 
spores.  These  are  really  vacuoles  or  degenerative  products.  True 
spore  formation  is  absent,  and  the  organism  does  not  ordinarily 
possess  any  capsule.  It  stains  easily  with  the  ordinary  aniline  dyes, 
especially  with  fuchsin,  but  is  Gram  negative. 

The  staining  is  not  always  uniform,  sometimes  irregular,  granu- 
lar (nuclear  chromatin).  The  bacillus  does  not  grow  in  characteris- 
tic arrangement.  Occasionally  two  rods  hang  end  to  end  (division 
forms)  and  even  short  chains  may  then  be  formed,  especially  in 
media  with  high  sugar  contents  in  which  its  motion  is  diminished. 

Ordinarily  the  bacillus  coli  is  actively  motile  in  varying  degree. 
The  movement  of  translation  in  space  is  usually  lazy  and  sluggish; 
it  never  acquires  the  rapid  movement  of  the  typhoid  and  paraty- 
phoids, although  when  virulent  the  motion  is  greater.  Its  flagellae, 
which  can  be  demonstrated  by  suitable  staining  methods,  are 
shorter,  fewer  and  more  delicate  than  in  the  typhoid  forms. 

Bacillus  coli  grows  well  on  gelatine  without  liquefaction.  Colonies 
are  characteristic,  leaf-like,  irregular,  white  or  milky.  It  resembles 
in  this  respect  the  typhoid,  but  grows  more  coarsely  and  thickly. 
On  agar  and  serum  it  also  grows  somewhat  like  the  typhoid,  but 
more  luxuriantly,  yellowish,  often  homogeneous.  Its  growth  on 
fresh  potato  is  quite  characteristic,  3  to  4  mm.  broad,  peasoup- 
like,  with  undulating  edges  (important  differential  from  typhoid — 
see  later).  It  develops  well  on  milk,  which  it  coagulates  (typhoid 
does  not).  In  broth  bacillus  coli  produces  a  strong  turbidity  (more 
so  than  typhoid)  in  an  alkaline  reaction.  The  odor  of  the  culture  is 
cheese-like,  but  not  foul. 

It  ferments  glucose,  mannite;  some  strains  also  saccharose,  dulcit 
and  glycerine  with  the  production  of  organic  acids.  Important  is 
the  production  of  CO2  and  H  gas  with  possible  traces  of  CH4.  This 
gas  production  commences  early  in  culture  (24  to  48  hours)  and  is 
most  marked  and  constant  on  glucose  and  lactose.  Saccharose  is  fer- 
mented to  acid  and  gas  in  about  60  per  cent.  (bac.  coli  communior). 
It  appears  that  this  is  a  true  fermentation  and  not  a  simple  hydro- 


36  GENERAL  PATHOLOGY 

lytic  cleavage.  It  takes  place  under  anaerobic  conditions  and  is 
more  complex  than  ordinary  yeast  fermentations.  Bioses  (sac- 
charose) are  probably  first  converted  into  mono-saccharides.  This 
gas  production  is  an  important  differentiation  of  the  colon  members 
in  contradistinction  to  entire  lack  of  gas  formation  by  the  typhoid 
bacillus. 

Gelatine  is  never  liquefied;  the  bacillus  is,  therefore,  not  proteo- 
lytic,  but  it  possesses  the  ability  to  split,  by  cleavage,  simpler  com- 
pounds from  the  protein  molecule.  Upon  this  property  depends  the 
important  formation  of  indol  and  skatol,  mercaptans,  ammonia 
and  H2S. 

In  anaerobic  environment,  the  organism  grows  in  the  presence 
of  glucose  (not  lactose)  with  the  formation  of  H.  Generally  speaking 
bacillus  coli  is  antagonistic  to  other  putrefactive  bacteria.  It  is  also 
resistant  to  drying  (150  to  200  days).  It  is  readily  killed  by  gastric 
juice  and  fresh  blood. 

The  great  variability  in  virulence  of  this  micro-organism  is  well 
shown  in  its  different  behavior  towards  animals,  so  that  a  general 
rule  cannot  be  laid  down.  In  moderately  large  doses  (2  to  3  c.c. 
of  fresh  broth  culture)  it  is  pathogenic  to,  and  even  kills,  animals 
with  symptoms  of  severe  gastro-enteritis,  somewhat  similar  to 
those  of  typhoid  fever,  but  less  pronounced.  Types  which  are  re- 
covered from  intestinal  diseases  are  reported  by  some  as  more 
virulent  than  others;  the  virulence  is  gradually  diminished  by 
cultivation. 

The  general  distribution  of  bacillus  coli  is  necessarily  a  very 
wide  one,  since  fields,  waters,  lakes,  rivers  are  almost  always  con- 
taminated by  it.  Even  pure  water  usually  contains  a  small  number. 
All  foodstuffs,  especially  milk  and  vegetables  and  those  that  under- 
go much  handling,  as  well  as  clothing,  are  contaminated  with  it. 
In  infants  on  the  breast  the  bacillus  coli  forms  almost  the  only 
intestinal  organism.  It  is  absent  in  the  upper  parts  of  the  gut,  while 
abundant  in  cecum  and  colon.  From  these  earliest  times  of  life  it 
persists  throughout.  Every  intestinal  catarrh  favors  its  develop- 
ment and  increase.  Ordinarily  it  leads  only  a  saprophytic  existence 
in  the  gut. 

The  pathogenic  importance  of  the  colon  bacteria  in  man  lies  in 


BACILLUS  COLI  COMMUNIS  37 

its  ability  to  pass,  under  certain  conditions,  through  the  gut  and 
invade  the  surrounding  structures  (peritoneum,  kidney,  etc.)  and 
even  the  circulation.  This  occurs  frequently  during  agony  and 
immediately  post-mortem  when  circulatory  stasis  and  tissue  death 
provide  no  longer  any  obstacles.  In  these  cases  the  appearance  of 
colon  bacilli  in  the  blood  and  organs  is  of  no  particular  significance. 
But  similar  favorable  opportunities  for  invasion  may  prevail  under 
certain  other  pathological  conditions  than  in  agony  and  death. 
Thus,  in  either  general  or  local  lowered  resistance,  entry  of  the 
colon  bacillus  in  large  numbers  through  the  gut  becomes  possible, 
and  it  may  then  acquire  pathogenic  importance,  either  by  itself 
or  as  partner  in  a  mixed  infection. 

This  pathogenic  importance  of  the  colon  bacillus  was  formerly 
overrated,  for,  as  we  have  already  seen,  its  presence  in  a  body  after 
death  may  be  the  result  of  agonal  or  post-mortem  invasion.  It 
is  the  merit  of  Gruber  to  have  pointed  out  that  agonal  or  post- 
mortem invasion  can  be  differentiated  from  true  infection  by  a 
peculiar  behavior  of  the  blood  serum  towards  a  diluted  broth  cul- 
ture of  the  bacillus.  In  true  infection  the  blood  serum  acquires  the 
ability  to  arrest  motion  and  agglutinate  (clump)  freshly  culti- 
vated colon  bacilli  in  very  high  dilutions.  This  can  be  observed  in 
hanging  drop  under  the  microscope.  These  dilutions  are  active 
when  the  normal  bactericidal  and  agglutinative  properties  of  blood 
serum  would  fail  and  thus  prove  true  interaction  between  micro- 
organism and  animal  body  by  presence  of  specific  agglutinative 
properties.  Gruber  discovered  here  an  important  immunological 
phenomenon  and  principle  which  will  be  discussed  fully  later, 
and  which  has  been  elevated  to  diagnostic  dignity  in  various  other 
diseases,  more  especially  in  typhoid  fever  by  Widal  (see  later). 

The  following  possible  infections  by  the  colon  bacillus  show  its 
varied  pathogenic  relations: 

1.  Septicemia,  more  particularly  in  infants  or  complicating  other 
infections. 

2.  Diarrheas  and  enteritis,  infectious  colitis,  especially  in  chil- 
dren. 

3.  Peritonitis,  after  severe  insults  (nutritive  or  inflammatory  or 
traumatic)  to  the  intestinal  wall. 


38  GENERAL  PATHOLOGY 

4.  Cholecystitis  and  production  of  gall  stones;  bile  stagnation 
is  favorable  to  infection  and  colon  bacilli  may  form  precipita- 
tion nuclei  for  concretions.  They  may  involve  the  liver  in  purulent 
inflammations  (liver  abscess). 

5.  Inflammation  of  genito-urinary  tract,  pyelitis,  cystitis;  in- 
fection is  favored  by  urine  stagnation.     Infection  occurs  through 
the  blood  stream,  but  also  directly  through  migration  from  the 
gut.     (Importance  of  intestinal  stasis.) 

6.  Pus  producer  especially  in  already  inflamed  and  infected 
organs  with  other  putrefactive  organisms. 

7.  In  eye  (conjunctivitis),  skin,  and  mouth  diseases. 


CHAPTER  VI 
BACILLUS  TYPHOSUS 

BACILLUS  TYPHOSUS.  The  disease  now  known  as  typhoid  fever 
has  been  recognized  from  very  early  times,  but  it  was  not  well 
defined  and  differentiated,  as  the  term  ru</>os  (fog)  was  given  to  a 
number  of  infectious  diseases  which  were  associated  with  clouded 
consciousness.  The  infection  was  considered  miasmatic  till  about 
1860  (Murchison).  Later  it  was  the  belief  that  bad  (sewer)  gases 
made  the  body  at  least  more  susceptible  to  the  disease.  The  bacil- 
lus was  discovered  by  Eberth  in  1880  in  the  mesenteric  glands  and 
spleen  of  typhoid  patients.  The  first  cultures  were  obtained  by 
Gaffky  in  1884.  The  chief  difficulty  in  its  recognition  was  the  simi- 
larity to  the  colon  bacillus  and  to  the  members  of  the  so-called 
paratyphoid  group,  and  in  1890  Koch  declared  that  an  absolute 
differential  between  these  types  did  not  exist.  Since  then  bacteri- 
ological and  especially  immunological  progress  has  cleared  these 
points.  Of  greatest  importance  is  here  the  phenomenon  of  specific 
serum  agglutination,  which  Gruber  used  in  establishing  true  colon 
infections  and  which  was  further  strengthened  by  the  observation 
of  Pfeiffer,  who  showed  that  the  serum  of  animals  made  immune  to 
a  disease  possessed  the  property  of  killing  and  dissolving  these 
bacteria  (Bacteriolysis — Pfeiffer's  phenomenon).  Widal  finally 
demonstrated  that  in  typhoid  fever  specific  agglutination  proper- 
ties against  typhoid  bacilli  develop  so  early  in  the  blood  of  typhoid 
patients  that  this  reaction  acquires  great  diagnostic  significance 
in  doubtful  cases  (Widal  reaction). 

The  bacillus  is  a  short,  plump  rod  of  varying  dimensions,  but 
less  so  than  the  bacillus  coli.  Like  the  colon  bacillus  it  is  negative 
to  Gram.  Important  is  its  great  motility,  which,  however,  is  depend- 
ent largely  upon  a  suitable  culture  medium,  especially  serum, 
peptonized  3  per  cent.,  glycerine  bouillon  and  dextrose  bouillon. 
Its  motion  is  oscillating,  serpentine  and  somersaulting,  and  is 

39 


40  GENERAL  PATHOLOGY 

executed  by  from  10  to  12  flagellae,  which  are,  therefore,  more 
numerous  than  in  the  colon  bacillus. 

It  forms  no  spores  and  grows  in  aerobic  and  anaerobic  environ- 
ment. As  a  general  differentiation  the  tyhoid  bacillus  grows  on  cul- 
ture media  less  luxuriantly  and  more  delicately  than  the  bacillus 
coli.  Gelatine  is  not  liquefied.  On  gelatine  plates,  small,  circular, 
oval  circumscribed  colonies  appear  in  24  hours,  colorless  at  first,  but 
after  48  hours  darker,  almost  brownish.  Later  it  grows  somewhat 
in  the  leaf-like  extension  of  the  colon  bacillus,  but  always  more 
delicately  and  with  a  characteristic  eccentric  dark  umbilication.  In 
bouillon  moderate  turbidity  is  produced,  Especially  important  is  its 
behavior  on  potato,  which  was  emphasized  by  Gaffky  and  before 
the  days  of  serology  was  one  of  the  most  reliable  differentiations. 
It  grows  on  potato  only  as  a  fine,  delicate,  often  hardly  visible, 
membrane  or  film.  Furthermore  it  does  not,  as  Kitasato  first 
pointed  out,  produce  indol  (see  above).  The  typhoid  bacillus 
grows  on  litmus  milk,  but  produces  less  acid  (bluish  red)  with 
very  often  a  terminal  alkalinity,  and  leaves  the  milk  clear  as 
contrasted  with  the  colon  bacillus  which  produces  much  acid 
(bright  red)  and  turbidity  in  milk  (coagulation). 

Very  important  is  the  lack  of  gas  fermentation  on  sugar,  not 
even  in  traces  (differentiation  from  paratyphoid  bacilli).  The  only 
other  bacillus  with  which  it  may  be  confounded  in  this  respect  is  the 
bacillus  fecalis  alkaligenes.  Lactose  and  saccharose  are  not  influenced 
by  the  typhoid  bacillus,  but  glucose,  maltose,  levulose,  galactose 
and  mannite  are  fermented  to  acid,  but  without  gas  formation. 

The  typhoid  bacillus  must,  therefore,  show  the  following  charac- 
teristics: (i)  active  motility,  (2)  Gram  negative,  (3)  growth  on 
gelatine  without  liquefaction,  (4)  faint  growth  on  potato,  (5)  no 
indol  production,  (6)  no  gas  fermentation  on  any  sugar,  (7)  growth 
on  litmus  milk  with  only  feeble  acid  formation  without  coagulation. 

Quite  difficult  at  times  may  be  its  identification  from  the  bacillus 
fecalis  alkaligenes  of  the  gut.  This  organism  resembles  the  typhoid 
very  closely,  but  shows  coarser  growth  on  potato  and  does  not 
form  acid  from  any  sugar.  The  paratyphoid  bacilli  also  do  not  pro- 
duce indol,  but  generally  ferment  sugar  with  the  formation  of  gas. 

Very  characteristic,  as  already  stated,  are  the  typhoid  reactions 


BACILLUS  TYPHOSUS  41 

with  the  serum  of  patients  or  convalescents.  Of  these  the  aggluti- 
nation (Widal  reaction)  has  practically  become  the  most  important. 
The  serum  of  immunized  individuals  possesses  in  large  dilutions 
(i  :ioo  or  even  more)  the  power  to  clump  freshly  cultivated,  active 
typhoid  bacilli.  Characteristic  are  only  high  dilutions,  as  even  nor- 
mal serum  has,  in  concentrated  form,  the  same  ability.  The  serum  is 
diluted  accurately  with  a  graduated  pipette  with  physiological  salt 
solution  and  then  added  to  a  measured  quantity  of  fresh  active 
broth  culture  of  typhoid  bacilli  to  obtain  the  desired  proportions. 
In  positive  agglutination  the  activity  of  the  bacilli  is  soon  dimin- 
ished, they  aggregate,  hang  together,  lose  their  motility  entirely 
(considered  by  some  the  essential  characteristic  of  the  reaction)  and 
finally  immobile  clumps  of  agglutinated  organisms  remain.  This  is 
the  end-reaction,  which  ought  to  occur  rapidly,  but,  of  course,  is 
dependent  somewhat  upon  the  degree  of  dilution.  In  practice  one 
usually  employs  dilutions  of  from  1 150  to  I  :ioo  when  agglutination 
should  be  complete  in  about  20  minutes  to  one-half  hour. 

To-day  the  diagnosis  by  blood  culture  is  often  easily  made  during 
the  life  of  the  patient  and  may  be  obtained  in  about  80  to  90  per 
cent,  of  the  cases  during  the  first  week  of  the  disease.  Gradually 
the  bacilli  disappear  in  the  course  of  the  illness.  Three  to  five  c.c.  of 
blood  from  a  vein  of  the  arm  should  be  immediately  transferred  to  a 
relatively  large  amount  of  culture  medium  (200  to  400  c.c.  of 
broth),  to  prevent  bactericidal  inhibitory  action  of  the  blood,  and 
incubated  without  delay.  Coleman  and  Buxton  have  introduced  the 
useful  method  of  cultivation  from  blood  on  ox  bile,  glycerine  and 
peptone. 

PATHOGENICITY.  The  typhoid  bacillus  is  not  infectious  to  ani- 
mals in  the  same  degree  as  it  is  to  man.  Its  growth  in  animals  is  ex- 
tremely limited.  Dead,  sterile  cultures  have  about  the  same  effect 
as  living  micro-organisms.  The  action  on  animals  is,  therefore,  only 
a  toxic  one.  The  bacilli  disappear  quickly  from  the  blood  and  do 
not  grow  in  internal  organs.  Local  infections  follow  injections  of 
large  doses  of  virulent  forms,  while  small  doses  are  rapidly  destroyed. 
For  man  the  bacillus  typhosus  is  truly  pathogenic.  Its  chief 
focus  of  action  and  port  of  entrance  is  the  lymphoid  tissue  of  the 
lower  ileum,  near  the  ileo-cecal  valve.  There  it  produces  swelling, 


42  GENERAL  PATHOLOGY 

especially  of  Peyer's  patches,  due  to  lymphoid  and  endothelial 
cell  proliferation  and  edema.  This  is  followed  by  necrosis,  sloughing 
anddesquamationofthe  parts,  leaving  a  bleeding  ulcer  in  the  longi- 
tudinal direction  of  the  gut.  The  bacilli  enter  the  mesenteric 
glands  and  produce  similar  changes  in  them.  They  are  also  abundant 
in  the  blood,  spleen,  bile  and  bone  marrow  and  in  the  characteristic 
skin  roseola.  Lymphoid  cell  foci  undergoing  necrosis  are  also  to 
be  found  in  liver  and  kidney.  Typhoid  fever  is,  therefore,  a  true 
septicemia  or  bacteriemia. 

Practically  of  importance  is  the  frequent  localization  of  typhoid 
bacilli  in  the  urinary  tract.  They  occur  in  the  urine  in  from  one-fourth 
to  one-third  of  all  typhoid  cases.  The  earliest  is  towards  the  end  of  the 
second  week,  often  later,  but  they  may  persist  during  convalescence 
and  even  after. 

This  appearance  is  frequently  very  abrupt,  so  that  the  urine 
may  be  clear  one  day  and  the  next  turbid  or  cloudy  with  bacilli. 
Albumin  and  blood  may  be  present,  but  not  necessarily,  and  the 
acid  urine  may  contain  only  few  leucocytes.  Rarer  are  cases  of  defi- 
nite typhoid  cystitis  and  pyonephritis.  The  urine  as  well  as  the 
feces  is,  therefore,  an  important  source  for  spreading  the  disease. 

The  bacilli  have  been  reported  to  persist  in  urine  for  several 
years  (up  to  five  years  by  Young).  Urotropine  is  efficient  in  clearing 
up  these  cases,  in  doses  of  from  1.5  to  3.0  gm.  per  day. 

In  the  gall  bladder  the  typhoid  bacilli  occur  frequently  and  grow 
well,  especially  when  the  bile  flow  is  interfered  with.  They  may  then 
produce  a  true  cholecystitis  and  this  may  not  make  its  appearance 
until  after  the  fever  itself  is  over.  The  bacilli,  like  bacillus  coli,  serve 
also  as  a  precipitation  nucleus  for  gall  stones.  They  are  very  persist- 
ent in  the  gall  bladder  and  have  been  recovered  7,  15  and  even  17 
years  after  a  typhoid  attack.  So-called  "typhoid  carriers"  who 
may  spread  the  disease  are  persons  of  this  type. 

Typhoid  bacilli  may  cause  complications  in  the  respiratory  tract 
in  the  course  of  typhoid  fever,  i.e.,  bronchitis  and  pneumonia. 
The  typhoid  septicemia  may  take  on  the  character  of  a  pyemia 
in  the  form  of  inflammatory  metastases  and  multiple  abscesses. 
These  may  be  of  two  kinds:  (i)  Due  to  the  typhoid  bacillus  itself; 
(2)  mixed  infections  with  cocci  as  secondary  invaders.  The  first 


BACILLUS  TYPHOSUS  43 

are  most  frequent  in  the  osseous  system  in  the  form  of  typhoid 
periostitis,  arthritis  or  osteomyelitis;  also  as  cause  of  tibial  abscesses 
and  of  necrosis  of  frontal  bone  in  the  skull.  These  may  occur  late 
in  the  disease,  even  in  convalescence.  Much  rarer,  according  to 
Curschmann,  are  subcutaneous  and  muscular  abscesses,  and,  very 
rare  are  inflammations  of  the  nervous  system.  The  old  idea  that  the 
typhoid  bacillus  is  never  a  pus  producer  is  no  longer  tenable,  al- 
though it  is  not  a  common  pus  former. 

Mixed  infections  in  typhoid  fever  are  rare.  These  may  occur 
either  as  more  or  less  independent  complications,  or  are  secondary 
on  the  ground  paved  by  the  typhoid  infection.  They  may  involve 
all  organs:  ear,  pleura,  parotid  gland,  peritoneum,  testicle  and 
prostate.  Typhoid  bacilli  are  here  absent  in  the  pus ;  only  strepto- 
cocci or  staphylococci  are  found. 

Typhoid  infections,  like  others,  vary  greatly  in  virulence  and  in 
the  extent  and  character  of  anatomical  lesions.  The  intestinal 
lymphoid  swelling  and  ulcerations  may  be  very  slight,  or  limited, 
sometimes  more  prominent,  or  entirely  confined  to  the  large  gut 
(colo-typhoid).  Perforation  of  intestinal  ulcers  is  frequent.  An 
important  feature  is  that  the  extent  and  severity  of  the  intestinal 
lesions  bear  no  relation  to  the  severity  of  the  disease.  Many  very 
severe  cases  show  relatively  slight  local  intestinal  changes  (ina- 
bility to  anchor  bacilli  in  gut),  being,  in  fact,  only  grave  typhoid 
septicemias. 

The  manner  of  transmission  and  infection  in  typhoid  is  by  direct 
ingestion  of  substances  contaminated  by  it,  usually  foodstuffs. 
The  importance  of  disinfection  and  proper  disposal  of  feces  and 
urine  is  plain,  and  the  possibility  of  infection  through  dejecta  of 
"carriers"  must  also  be  recognized.  Persons  long  recovered  and 
quite  well  but  who  harbor  typhoid  bacilli  in  the  gall  bladder 
or  urinary  bladder  may  for  many  years  spread  the  infection 
wherever  they  go. 

It  has  not  been  possible  to  demonstrate  a  particular  toxic 
secretion  in  typhoid  bacilli,  which,  as  in  diphtheria,  is  distinct 
and  separable  from  the  bacillary  body  (esotoxine).  The  typhoid 
toxemia  is  evidently,  at  least  largely,  dependent  upon  toxines 
liberated  by  disintegration  of  the  bacilli  themselves  (endotoxine). 


CHAPTER  VII 
PARATYPHOID  BACILLI 

IT  is  now  well  established  that  diseases  occur  which  clinically, 
anatomically  and  bacteriologically  are  closely  allied  to  typhoid, 
but  differ  in  certain  respects.  Bacteriologically  this  group  stands 
between  the  colon  and  typhoid  bacilli  with  similarities  and  slight 
morphological  differences  between  the  members  of  each  group. 
Clinically  they  show  often  a  lighter,  more  irregular  course  than 
typhoid,  with  a  mortality  of  below  i  per  cent.  Two  main  cultural 
characteristics  distinguish  generally  paratyphoid  from  typhoid 
and  colon  bacilli.  They  ferment  sugars  to  gas,  as  opposed  to  ty- 
phoid, but  do  not  produce  indol,  as  opposed  to  colon  bacilli.  In 
their  motility  they  resemble  closely  the  typhoid. 

TABLE  II 


B.  COLI 

TYPHOID 

PARA- 
TYPHOID 

Motility 

Sluggish 

Active 

Active 

Gas  production  from  sugar  

+4- 

o 

+  + 

(Not  from 
lactose) 

Acid  production  from  sugar  .  .        

4- 

+ 

4- 

(Not  from 
lactose) 

(Not  from 
lactose) 

Indol 

4-4- 

o 

o 

Milk  coagulation  

+ 

o 

0 

Growth  in  potatoes  

Luxuriant 

Delicate 

Variable 

Agglutination  

Specific 

Specific 

Specific 

Gram  

Negative 

Negative 

Negative 

Two  groups  of  paratyphoid  bacilli  are  recognized,  A  and  B.  B 
occurs  in  the  larger  number  of  cases  of  paratyphoid.  These  groups 
differ  in  relation  to  alkali  production  in  milk  and  sugar  fermen- 

44 


PARATYPHOID  BACILLI  45 

tations.  Type  A  produces  alkali  in  litmus  milk  (after  slight  pri- 
mary acidity)  more  slowly  than  type  B  (14  days  in  A;  four  to 
five  days  in  B).  A  ferments  xylose  and  dulcite  slowly.  B  ferments 
xylose  and  dulcite  rapidly.  A  does  not  blacken  lead  acetate  in  18 
to  24  hours.  Pathogenetically  A  resembles  closely  typhoid,  and  is 
less  toxic  to  animals. 

Some  paratyphoids  seem  to  be  able  to  lead  a  saprophytic  exis- 
tence in  the  gut.  Their  exact  biologic  relation  to  typhoid  and 
colon  bacilli  has  not  been  determined. 

BACILLUS  ENTERITIDIS  OF  GARTNER.  This  is  one  of  the  im- 
portant paratyphoid  members,  and  is  responsible  for  many  meat 
infections.  It  has  been  known  for  a  long  time  that  the  ingestion 
of  apparently  healthy,  non-putrefied  meat,  may  produce  serious 
gastro-enteritis,  often  with  marked  nervous  symptoms  and  other 
evidence  of  general  infection.  The  disease  commences  about  six 
to  twelve  hours  after  ingestion  with  nausea,  vomiting,  and  diar- 
rhea. A  number  of  cases  result  fatally,  and  autopsy  then  discloses 
the  anatomical  lesion  of  a  severe  gastro-enteritis  with  swelling 
of  the  lymphoid  tissue  of  the  gut  and  spleen  and  degenerative 
nephritis.  The  disease  is  much  more  apt  to  arise  after  partaking 
of  raw  or  insufficiently  cooked  meat,  although  it  occurs  some- 
times even  after  eating  cooked  meats  (toxine  action). 

Gartner  succeeded,  in  1888,  in  isolating  a  pathogenic  organism 
from  the  meat  of  a  cow,  the  ingestion  of  which  had  been  followed 
by  toxic  symptoms.  He  obtained  an  identical  organism  from  the 
spleen  of  a  person  who  died  after  eating  this  meat.  Both  resembled 
the  typhoid  bacillus  in  some  respects,  and  the  colon  bacillus  in 
others.  A  similar  bacillus  was  identified  in  subsequent  epidemics 
of  meat  poisoning  in  1 890  and  1 892,  and  further  studies  showed  its 
close  relation  to  certain  other  animal  diseases,  notably  pneumo- 
enteritis  of  calves,  and  hog  cholera. 

The  most  impressive  epidemic  caused  by  Gartner's  bacillus 
took  place  in  Ghent,  Belgium,  in  1 895,  and  was  thoroughly  studied 
by  van  Ermengem.  The  inspector  of  an  abattoir,  who  himself  was 
an  expert  veterinarian,  had  been  ordered  by  the  police  to  examine 
a  number  of  smoked,  so-called,  "Cervelat"  sausages,  because 
suspicion  had  become  strong  that  these  sausages  had  been  respon- 


46  GENERAL  PATHOLOGY 

sible  for  disease  in  several  consumers.  The  inspector  was  under 
the  belief  that  only  putrefied  meat  was  dangerous  and  when  he 
saw  the  perfectly  fresh,  sweet  material,  passed  it  as  safe,  himself 
ate  some  of  it,  and  also  distributed  it  amongst  employees.  All 
were  taken  ill;  the  inspector  with  fatal  results.  He  died  in  five 
days,  with  all  the  symptoms  of  meat  poisoning.  From  the  body 
of  this  veterinarian  and  from  the  sausages  van  Ermengem  isolated 
Gartner's  bacillus.1 

In  an  epidemic  occurring  in  1892  in  Paris,  observed  by  Leichten- 
stern,  Nocard  isolated  a  paratyphoid  organism.  The  disease  was  a 
pneumonia  with  typhoid  symptoms  and  probably  conveyed  to  man 
by  parrots.  It  has,  therefore,  been  named  psittacosis.  In  a  number 
of  cases  of  infections  with  paratyphoid  bacillus  B,  ulcerative  lesions 
in  the  large  gut  resembling  dysentery  have  been  observed. 

1  This  form  of  meat  infection  must  be  strictly  distinguished  from  botulism, 
which  is  excited  by  another  organism,  the  bacillus  botulinus,  a  pathogenic 
saprophyte  and  strict  anaerobe.  This  Gram-positive  bacillus  does  not  grow 
in  the  living  body,  but  thrives  on  dead  organic  material,  which  has  been 
contaminated  by  it,  under  exclusion  of  air  (insufficiently  sterilized  canned 
meat,  fish  and  vegetables).  In  them  it  produces  an  extremely  toxic  poison 
which  is  fatal  in  many  instances  in  which  such  food  insufficiently  cooked,  has 
been  consumed.  The  poison  affects  the  nervous  system  producing  dyspnea, 
delirium  and  paralysis.  One  to  two  drops  from  a  gelatine  culture  are  suffi- 
cient to  kill  an  ordinary  monkey,  0.0003  to  o.ooi  c.c.  is  sufficient  to  kill  a 
rabbit,  and  from  o.oooi  to  0.0005,  a  guinea  pig.  The  poison  seems  to  be  related, 
and  acts  similar,  to  that  of  certain  mushrooms  and  the  tetanus  toxine. 


CHAPTER  VIII 
BACILLUS  DYSENTERIC 

BACILLUS  DYSENTERI/E.  There  exist  a  number  of  infective 
organisms  in  relation  to  dysentery,  some  of  which  are  not  even 
bacteria,  but  protozoa.  Since  the  discovery  of  the  ameba  coli  by 
Koch  and  Kartulis  in  Egypt,  which  was  later  confirmed  by  Osier, 
Councilman  and  Lafleur,  and  others,  amebic  dysentery  has  come 
to  be  recognized  as  a  tropical  disease.  In  1898  Shiga,  however, 
described  a  bacillus  which  has  acquired  great  importance  in  its 
relation  to  the  dysentery  of  Northern  countries. 

This  organism  was  first  identified  by  Shiga  in  an  epidemic  in 
Japan ;  by  Kruse,  two  years  later,  in  a  similar  epidemic  in  Rhenish 
Westfalia,  and,  finally,  by  Flexner  and  Strong  in  the  Philippines. 
While  all  of  the  bacilli  which  were  recovered  in  various  parts  of  the 
world  were  held  at  first  to  be  identical,  it  is  now  known  that  they 
represent  various  types  and  are,  as  a  class,  closely  related  to  the 
colon  typhoid  group. 

Anatomically  dysentery  is  characterized  by  a  necrotic  diphthe- 
ritic inflammation  of  the  large  gut  (ulcerative  colitis).  The  inflam- 
mation is  first  catarrhal,  but  soon  becomes  intense  and  leads  to 
necrosis  of  the  inflamed  parts  and,  by  sequestration,  to  irregular 
ulcerations.  In  amebic  dysentery  the  ulcers  are  said  to  show  a  char- 
acteristic undermining  of  edges,  while  in  bacillary  dysentery  the 
ulcers  are  flat  and  irregular.  These  ulcers  heal  with  abundant  scar 
formation  and  are  often  followed  by  contraction  and  stenosis  of 
the  gut.  Other  viscera  are  hardly  involved  in  bacillary  dysentery, 
whereas  in  the  amebic  type  liver  abscess  is  a  frequent  sequel. 

The  Shiga  bacillus,  which  is  the  prototype  of  the  bacillus  dysen- 
teriae  group,  is  a  short  rod,  which  resembles  the  typhoid  bacillus, 
but  is  plumper  and  polymorphous  in  culture.  It  is  Gram  negative, 
but  stains  well  with  aniline  dyes.  It  was  originally  thought  by  Shiga 
and  Flexner  that  the  organism  was  motile,  but  later  investigations 

47 


48  GENERAL  PATHOLOGY 

iave  demonstrated  that  the  motility  is  probably  only  active 
kownian  movement.  Flagellae  have  not  been  demonstrated. 

ic  dysentery  bacilli  grow  well  on  the  usual  culture  media  under 
aerobic  and  anaerobic  conditions.  Growth  on  potato  is  similar  to 
typho| d.  Gelatine  is  not  liquefied ;  indol  is  not  formed  by  the  Shiga, 
but  by  some  other  types;  glucose  is  not  fermented  to  gas.  Milk  is 
slightly  acidified,  but  not  coagulated.  The  growth  on  gelatine  shows 
a  leaf-like  extension,  not  unlike  that  of  typhoid,  and  quite  delicate. 

Differentiation  of  the  various  types  of  dysentery  bacilli  is  largely 
based  on  their  behavior  towards  sugars  and  specific  agglutination 
reactions.  The  Shiga  bacillus  does  not  produce  acid  on  mannite, 
the  Flexner-Strong  bacillus,  recovered  in  Manila,  and  some  others, 
do.  Some  produce  also  acid  from  maltose  and  saccharose.  All  mem- 
bers of  the  group  produce  acid  from  glucose.  Life  in  culture  is  short 
and  the  organism  is  easily  overgrown  by  other  bacteria;  it  also  suc- 
cumbs to  drying  in  12  to  17  days.  In  moist  ground,  if  protected 
from  direct  sunlight,  it  may  remain  viable  for  months.  In  the 
human  body  it  seems  also  to  persist  for  a  long  time.  It  is  found  in 
the  gut  of  persons  ill  with  the  disease,  in  the  ulcers  and  mesenteric 
glands,  but  not  in  the  spleen,  blood,  urine  or  milk.  Its  action  seems, 
therefore,  to  be  largely  local  and  not  invasive. 

The  importance  of  dysentery  lies  in  its  epidemic  occurrence. 
Wherever  masses  of  people  aggregate  (armies)  under  unsanitary 
conditions,  there  exists  danger  of  outbreak  of  dysentery.  It  attacks 
with  predilection  the  weak,  reduced  and  decrepit.  It  is  easily  con- 
veyed by  intestinal  discharge  and  soiling  of  clothing,  bedding, 
etc.;  possibly  also  by  flies.  Drinking  water  and  rivers  are  easily 
polluted  (carriers). 

Infection  occurs  probably  by  mouth.  Strong  and  Musgrave  re- 
port direct  infection  of  a  criminal  who  swallowed  a  48-hour  broth 
culture  after  neutralization  of  his  gastric  contents  by  weak  sodium 
hydrate.  He  developed  symptoms  and  the  discharge  of  dysentery  in 
36  hours.  The  organism  was  isolated  from  the  stools.  Similar  re- 
sults were  obtained  by  Ravant  and  Dopter  in  feeding  monkeys. 


CHAPTER  IX 

CAPSULATED  BACILLI— BACILLUS  LACTIS  AEROGENES 
-THE  PROTEUS  GROUP 

CAPSULATED  BACILLI.  A  number  of  capsulated  bacilli,  more  or 
less  related  to  the  colon  typhoid  group,  are  of  importance.  The 
prototype  of  this  class  is  the  following: 

Bacillus  Mucosus  Capsulatus. — Also  called  Friedlander's 
bacillus.  It  was  found  in  1882  by  Friedlander  in  cases  of  pneumonia 
and  described  as  pneumonic  bacillus.  Only  a  relatively  small  num- 
ber of  pneumonias,  however,  are  caused  by  it  (8  to  10  per  cent.),  the 
bulk  being  due  to  the  pneumococcus.  It  is  very  virulent  and  the 
pneumonic  exudate  is  more  serious,  tenacious,  but  less  fibrinous  than 
that  caused  by  the  pneumococcus.  The  bacillus  is  a  short,  plump 
rod  (0.5  to  1.25/x  broad  and  only  0.5  o  o.6ju  long),  sometimes  as 
broad  as  long,  coccoid  bacilli. 

It  is  non-motile,  does  not  form  spores,  is  easily  cultivated,  grows 
under  aerobic  and  anaerobic  conditions  (better  aerobic),-  and 
possesses  a  definite  broad  capsule  in  recent  state.  Artificially  culti- 
vated, the  capsule  is  retained  only  during  the  first  generation,  but 
may  be  reproduced  by  renewed  animal  inoculation.  The  organism 
is  Gram  negative.  Cultivation  is  possible  between  10°  to  I2°C.  and 
56°C.  The  colonies  show  a  characteristic  slimy,  tenacious,  stringy 
appearance.  Gelatine  is  not  liquefied.  Indol  is  not  produced  and 
milk  may  or  may  not  be  coagulated.  Cultural  behavior  towards 
sugars  is  variable. 

Bacillus  Rhino-Scleroma. — This  organism  is  morphologically 
closely  related  to  Friedlander's  bacillus  and  is  by  some  believed 
to  be  identical  with  it.  Rhino-scleroma  is  a  slowly  progressing 
granulomatous  inflammation  of  the  external  nares  and  mucosa  of 
nose,  mouth  and  larynx.  Microscopically  it  is  characterized  by 
thick,  connective  tissue  formation  with  bright,  hyaline  cells  within 
its  meshes  which  contain  the  bacilli.  Rare  in  America. 

4  49 


50  GENERAL  PATHOLOGY 

BACILLUS  LACTIS  AEROGENES.  This  has  already  been  mentioned 
in  connection  with  the  colon  bacillus.  It  was  first  described  by 
Escherich,  in  1885,  with  the  colon  bacillus,  as  occurring  in  the 
upper  intestinal  tract  of  infants.  It  produces  gas  energetically  on 
sugar  broth  and  invariably  coagulates  milk.  It  is  found  constantly 
in  the  human  intestine.  It  is  a  facultative  anaerobe  and  produces 
acid  on  lactose  media.  Gas  production  in  the  gut  may  be  strong 
enough  to  give  rise  to  flatulence. 

THE  PROTEUS  GROUP.  This  is  a  very  widely  distributed  group 
which  is  not  of  very  great  pathogenic  importance,  except  for  its 
activity  in  the  intestinal  tract.  The  members  of  the  group  bear  a 
certain  resemblance  to  the  bacillus  coli,  but  are  longer  and  slender, 
with  a  tendency  to  form  filaments.  They  are  motile  and  possess 
numerous  flagellae.  The  prototype  of  the  group  is  bacillus  proteus 
vulgaris,  discovered  by  Hauser.  It  is  Gram  negative.  On  gelatine 
growth  takes  place  from  a  center  in  characteristic  radiating  threads. 
Gelatine  is  liquefied,  somewhat  less  readily  under  anaerobic  condi- 
tions. On  solid  agar  colonies  grow  in  irregular  sausage,  corkscrew- 
like  streamers  over  the  surface,  giving  the  growth  somewhat  of  a 
stellate  appearance. 

The  chief  function  of  the  bacillus  proteus  is  putrefactive,  split- 
ting the  proteid  molecule  into  its  simplest  radicles.  Its  pathogenic 
importance  rests  mainly  in  some  diarrheal  diseases. 


CHAPTER  X 
BACILLUS  DIPHTHERIA,  DIPHTHEROIDS 

THE  disease  now  recognized  as  diphtheria  is  of  importance  not 
only  as  a  disease  of  wide  distribution,  but  because  it  was  the  first 
infectious  disease  in  which  modern  science  established  practical 
control  by  an  enormous  reduction  in  morbidity  and  mortality. 
Moreover,  it  was  this  disease  which  led  to  the  foundation  of  modern 
conceptions  of  immunity.  For  the  first  eventful  study  of  bacterial 
toxines  and  anti-toxines  was  carried  on  in  diphtheria  and  serum 
therapy  was  introduced. 

While  the  malignant  diseases  of  the  throat  have  been  known  for 
generations,  and  have  frequently  occurred  in  severe  and  devastat- 
ing epidemics,  it  was  Bretonneau  of  Tours  who  recognized  diph- 
theria in  the  modern  sense  of  an  infectious,  pseudo-membranous 
angina  or  croup.  Until  the  work  of  Bretonneau,  croup  and  diph- 
theria were  regarded  as  two  distinct  affections.  Napoleon  the  first, 
after  the  death  of  his  nephew,  had  offered  a  prize  for  the  best 
essay  on  the  nature  and  treatment  of  croup.  Thus,  following  an 
epidemic  in  Tours,  Bretonneau  (1818-1820)  disclosed  by  autopsy 
the  essential  anatomical  similarity  and  relationship  between  all 
the  pseudo-membranous  inflammations  of  the  pharynx  and  larynx 
and,  on  account  of  the  general  presence  of  a  false  membrane  made 
up  of  exuded  fibrin,  which  fuses  with  coagulated  dead  masses  of 
mucous  membrane,  gave  these  inflammations  the  term  diphtherite 
(from  bl$Qkpa  =  membrane).  Later  Virchow  employed  the  terms 
croupous  and  diphtheritic  purely  in  a  general  anatomical,  not  in 
an  etiological,  sense.  He  spoke  of  "croup"  as  an  inflammation  of 
mucous  membranes  in  which  a  fibrinous  exudate  is  precipitated  on 
a  necrotic  surface,  and  of  "diphtheritic  inflammation  "  when  this  is 
accompanied  by  death  of,  and  fusion  with,  deeper  layers  of  the 
mucous  membrane. 

51 


52  GENERAL  PATHOLOGY 

Diphtheritic  inflammation  is,  therefore,  anatomically,  the  se- 
verer, more  destructive  process  of  the  two.  Virchow  attached  to 
these  terms  purely  a  descriptive  anatomical  meaning  without 
reference  to  a  particular  etiological  factor  or  any  particular  locality. 
A  good  deal  of  confusion  has  arisen  in  their  use  since  the  discovery 
of  a  specific  micro-organism  by  Loffler,  called,  unfortunately,  the 
diphtheria  bacillus.  This,  it  has  been  found,  is  etiologically  con- 
cerned in  some,  but  not  all  pseudo-membranous,  croupous  or  diph- 
theritic inflammations  of  the  throat  and  elsewhere,  and  it  does  not 
always  produce  a  pseudo-membranous  inflammation,  but  occasion- 
ally only  a  simple  angina  of  the  pharynx.  The  suggestion  has, 
therefore,  been  made  to  drop  the  name  diphtheria  for  the  specific 
anginas  or  pseudo-membranous  inflammations  of  the  throat, 
caused  by  Loffler's  bacillus  altogether,  and  to  speak  of  them  as  was 
done  centuries  ago  as  synanche  contagiosa  (Senator,  Orth).  The 
term  diphtheria  appears,  however,  so  deeply  rooted  in  lay  and  medi- 
cal usage  that  this  has  met  with  no  success. 

The  organism  was  definitely  identified  by  Loffler  in  1 884,  but  had 
already  been  noted  by  Klebs  in  1883  in  pseudo-membranous  exu- 
dates.  It  is,  therefore,  sometimes  spoken  of  as  Klebs-Loffler  bacillus. 
The  organism  is,  as  the  name  signifies,  a  rod,  straight  or  partly 
curved  and  often  with  a  club-shaped  swelling  at  one  extremity.  It 
is  about  6/-1  long  and  i.6/x  thick,  non-motile  and  stains  particularly 
well  with  alkaline  methylene  blue  (Loffler's  Solution):  Saturated 
alcoholic  Sol.  of  methylene  blue,  30  gm.  Sol.  of  caustic  potash, 
1.10,000,  100  c.c. 

Characteristic  is  its  pleomorphism  and  the  marked  irregularity 
with  which  it  takes  stains.  The  rod  is  pale,  often  colorless,  while  at 
the  poles  appear  deeply  staining  points,  or  paler  granules  espe- 
cially in  bacilli  which  have  been  grown  on  blood  serum.  Neisser  has 
introduced  the  following  staining  method  for  demonstration  of 
these  granules. 

i.  Stain  one  to  two  seconds  in  a  solution  of  i  gm.  methylene 
blue  (Griibler),  dissolved  in  20  c.c.  96  per  cent,  alcohol.  Add  950 
c.c.  H2O  +  50  c.c.  glacial  acetic  acid,  filter.  (2)  Wash  in  water.  (3) 
Stain  for  three  to  five  seconds  in  a  solution  of  Bismarck  brown, 
(Vesuvin)  2  gm.  in  100  c.c.  of  boiling  H2O.  (4)  Wash  and  mount. 


BACILLUS  DIPHTHERIA  53 

The  bacilli  appear  as  pale  brown  rods,  bearing  bluish  black 
(metachromatic)  granules,  usually  of  an  oval  shape  and  of  some- 
what greater  diameter  than  the  rod.  While  they  are  generally  polar, 
they  occur  also  in  the  center  of  the  bacillary  body  and  are  spoken  of 
as  Babes-Ernst  granules.  The  character  of  these  granules  has  been 
a  source  of  discussion.  Originally  Ernst  regarded  them  as  spores, 
but  to-day  it  is  generally  held  that  this  differentiation  of  the  bac- 
terial plasma  with  the  formation  of  the  granules  has  nothing  to  do 
with  propagation,  but  is  an  expression  of  cell  metabolism. 

Culture.  For  a  reliable  diagnosis  of  this  organism,  culture  on 
an  appropriate  medium  is  indispensable.  The  bacillus  is  in  need  of 
much  O.  It  grows  best,  therefore,  on  the  surface  of  slanted,  solid 
media  containing  protein  at  usual  temperature  and  alkaline  reac- 
tion. The  blood  serum  recommended  by  Loffler  is  best.  On  this,  bacilli 
grow  rapidly  in  12  hours  to  small,  opaque  colonies.  After  24  to  48 
hours  these  fuse  to  a  thick,  white  mantle  on  the  solid  serum.  Growth 
on  agar  is  also  good,  especially  with  blood  serum  and  glucose.  On 
nutrient  gelatine  development  is  slower  and  less  luxuriant. 

In  nutrient  broth  flocculent  turbidity  occurs  in  12  to  24  hours, 
and  precipitation  with  acid  formation  in  48  hours.  The  acidity  in- 
hibits the  formation  of  the  toxine.  On  milk,  growth  is  as  good  as  in 
broth  producing  no  coagulation.  On  potato,  development  is,  on  ac- 
count of  strong  acid  production,  poor.  Blood  serum  culture  is,  there- 
fore, best  for  diagnosis  and  can  be  made  in  about  12  to  20  hours.  But 
it  must  be  remembered  that  in  about  10  per  cent,  of  advanced  or 
older  cases  in  which  the  pseudo-membrane  is  about  to  desquamate 
the  bacilli  can  no  longer  be  recovered  by  culture.  The  earlier 
bacteriological  examination  of  a  suspected  throat  is  made,  the 
better. 

Resistance  of  bacilli  on  blood  serum  is  great.  LofHer  succeeded 
in  growing  them  in  full  virulence  for  27  months  in  77  replantations. 
Membranes  containing  bacilli  retain  them  long  (3  to  4  months) 
even  when  dry  but  not  exposed  to  light.  In  dry  air  they  die  in  a  few 
days,  even  hours.  Small  pieces  or  fragments  of  membrane  coughed 
upon  objects  like  toys,  chairs,  clothing,  etc.,  or  attached  to  spoons, 
knives,  forks,  or  even  dust  may  carry  the  infection.  The  organism 
is  very  susceptible  to  heat  (killed  by  6o°C.)  and  oxidizing  agents, 


54  GENERAL  PATHOLOGY 

notably  H2O2  and  formaldehyde  (these  are,  therefore,  valuable 
disinfectants). 

Virulent  bacilli  may  remain  in  the  nasopharynx  for  a  long  time 
after  desquamation  and  cause  infection  in  others.  It  is  the  custom 
in  some  hospitals  for  infectious  diseases  to  discharge  no  patient 
until  swabs  from  the  throat  are  shown  to  be  bacilli  free.  It  is  in 
this  connection  important,  that,  especially  during  an  epidemic, 
nurses,  orderlies  and  others  in  contact  with  patients  may  harbor 
and  carry  bacilli  in  their  mouths,  although  themselves  not  ill 
(carriers).  Even  other  persons,  not  directly  in  contact  with  pa- 
tients, may  do  so.  Thus,  Park  found  that  i  per  cent,  of  healthy 
throats  examined  in  New  York  during  an  epidemic  carried  bacilli. 
Great  care  must,  therefore,  be  exercised  to  prevent  spread  of  this 
infection. 

The  virulence  and  consequent  local  and  general  effects  of  the 
bacillus  also  show  great  individual  differences.  In  some  the  disease 
may,  as  already  stated,  produce  only  a  slight  angina  with  little 
constitutional  effects,  in  others  it  appears  as  a  severe,  septic  pseudo- 
membranous  inflammation  of  the  throat,  larynx  and  trachea,  extend- 
ing to  the  bronchi.  One  and  the  same  strain  may  cause  in  one  person 
only  slight  reaction  and  in  another  malignant  fatal  results.  Here, 
as  elsewhere,  secondary  infections,  especially  with  streptococci, 
play  a  large  role. 

Patbogenicity.  The  pathogenic  action  of  this  bacillus  is  partic- 
ularly characteristic  in  guinea  pigs.  After  subcutaneous  injec- 
tion of  3^  to  i  c.c  of  a  24-hour  broth  culture,  these  animals 
become  visibly  ill,  lose  their  appetite  and  succumb  in  two  to 
three  days.  At  the  place  of  inoculation  a  gelatinous,  edematous 
hemorrhagic  inflammation  of  the  subcutaneous  tissue,  containing 
numerous  bacilli,  is  found  which  often  extends  deeper,  involves  the 
musculature  and  assumes  a  general  extension  (abdomen  and  chest) . 
The  inguinal  glands  are  swollen  and  hemorrhagic  and  the  abdominal 
cavity  contains  serous,  hemorrhagic  exudate.  Especially  character- 
istic is  the  great  inflammatory  enlargement  of  the  suprarenal  gland. 
It  is  deeply  reddened  and  shows  numerous  hemorrhages.  The  omen- 
turn  also  shows  abscesses  with  bacilli,  and  the  pleurae  are  the  seat 
of  a  double  exudative  pleurisy,  sometimes  sufficient  to  float  both 


BACILLUS  DIPHTHERIA  55 

lungs  in  the  fluid.  Besides  these  acute  fatal  manifestations  the 
infection  may  pursue  a  more  chronic  course. 

In  other  animals,  notably  rabbits,  inoculation  into  the  trachea 
leads  to  a  pseudo-membranous  inflammation  with  dyspnea  and 
death  or  a  late  paralysis.  In  man  it  is  possible  to  recognize  three 
expressions  of  this  infection,  (i)  the  localized  diphtheritic  lesion; 
(2)  the  general  diphtheritic  infection;  (3)  the  septic  and  gangre- 
nous diphtheria. 

1.  Localized  Lesion.     It  has  already  been  emphasized  that  infec- 
tions with  the  so-called  diphtheria  bacillus  of  Loffler  does  not 
necessarily  lead  to  what  is  anatomically  a  diphtheritic  inflamma- 
tion. All  grades  and  transitions,  from  angina  pharyngis  to  severe 
necrotic  exudative  inflammations  in  which  the  exuded  fibrin  fuses 
with  the  necrotic  masses  to  form  a  densely  adherent  pseudo-mem- 
brane,  may  occur.   Characteristic  of  the  latter  is  often   rapid 
development   and    extension.    This    was  already  recognized  by 
Bretonneau. 

2.  General   Infection.     The   general   diphtheritic   infection   de- 
pends upon  poisoning  with  a  toxine  set  free  by  the  bacilli  (eso- 
toxine).  The  earlier  investigators,  among  them  Loffler  himself, 
had  already  concluded  that  the  severity  of  the  symptoms  and 
even  some  of  the  anatomical  changes  in  the  body  could  hardly  be 
due  to  local  bacterial  action,  and  suspected  a  poison.  Loffler  even 
succeeded  in  extracting  with  glycerine  and  subsequent  precipi- 
tation by  alcohol,  a  poisonous  substance  from  broth  cultures 
which  produced  local  inflammatory  reactions.  But  it  was  the  work 
of  Roux  and  Yersin  to  put  the  knowledge  of  diphtheritic  toxine 
on  a  sound  basis.  They  filtered  a  fresh  broth  culture  through  a 
Chamberlain  filter,  thus  rendering  the  filtrate  germ  free.  This  ster- 
ile filtrate  was  injected  into  guinea  pigs  and  rabbits  in  relatively 
large  doses,  up  to  35  c.c.  with  very  definite  toxic  results;  loss  of 
appetite,  dyspnea  and  death  in  five  to  six  days. 

Autopsy  disclosed  the  characteristic  inflammatory  involvement 
of  the  suprarenal  gland  and  serous  pleurisy.  Animals  which  sur- 
vived showed  later  paralysis.  Older  broth  cultures  were  more 
active  and  fatal  even  to  larger  animals  like  dogs.  White  mice, 
which  are  ordinarily  not  susceptible  to  the  bacilli  themselves,  are 


56  GENERAL  PATHOLOGY 

killed  by  toxine  doses  which  are  sufficient  to  kill  80  guinea  pigs 
(relative  immunity).  The  poison  develops  best  in  alkaline  broth 
with  free  access  of  air.  Acid  reaction  is  detrimental  to  its  production. 
The  observations  of  Roux  and  Yersin  have  subsequently  been 
generally  confirmed  and  enlarged.  Especially  important  in  this 
respect  is  the  fact  that  the  formation  of  the  poison  is  proportional 
to  the  virulence  of  the  bacilli.  It  is  destroyed  by  a  temperature  of 
6o°C.  but  not  by  evaporation  at  5O°C.,  or  treatment  with  HCI. 
It  is,  therefore,  no  ferment  or  enzyme.  It  is  precipitated  by  NH4OH 
or  NaSO4  from  bouillon  cultures  and  may  be  cleaned  by  dialysis 
(Brieger  and  Frankel).  On  account  of  certain  protein  reactions  it 
was  formerly  regarded  as  a  toxalbumen,  but  it  has  been  found 
that  the  albuminous  contents  are  only  an  admixture  and  that  the 
poison  may  be  freed  from  the  albumen  complex.  It  is,  moreover, 
easily  oxidized.  The  chemical  nature  of  the  poison  is  at  present 
quite  obscure.  Unlike  the  action  of  ferments,  the  quantity  adminis- 
tered stands  in  direct  proportion  to  the  poisonous  properties. 
Kossel  has  shown  that  the  poison  is  originally  intimately  connected 
with  the  bacillary  body  and  gradually  dissolves  in  the  culture 
medium  by  maceration,  so  that  it  is  present  in  greatest  quantity 
when  the  bacilli  decline  in  growth  and  activity. 

3.  Septicemic  Type.  Loffler  had  already  appreciated  that  the 
diphtheria  bacilli  pave  the  way  for  the  entrance  of  other  bacteria, 
notably  streptococci.  Thus  the  septicemic  form  of  diphtheria 
follows,  really  a  mixed  infection  in  which  the  local  diphtheritic 
lesion  has  opened  blood  and  lymph  channels  for  invasion  by  other 
bacteria.  The  diphtheria  bacilli  themselves  remain  superficial, 
do  not  penetrate  and  do  not,  at  least  in  any  quantity,  enter  the 
blood  stream  or  permeate  the  viscera. 

In  these  mixed  infections  the  deepest  and  most  extensive  involve- 
ment of  the  respiratory  passages  occur.  Nose,  ear,  the  accessory 
sinuses  and  trachea  and  bronchi  may  be  covered  by  a  thick  pseudo- 
membrane  and  this  may,  by  desquamation,  become  really  dangerous 
as  a  mechanical  impediment  to  breathing,  and  kill  through  as- 
phyxia (this  occurs  sometimes  in  neglected,  advanced  diphtheria 
after  a  large  dose  of  antitoxine,  when  the  pseudo-membrane  is 
rapidly  loosened).  Broncho-pneumonia  occurs  in  about  50  per  cent. 


BACILLUS  DIPHTHERIA  57 

of  fatal  cases.  There  is  danger  of  myocarditis  with  sudden  heart 
paralysis  and  it  may  even  later  lead  to  trouble  in  causing  ex- 
tensive myocardial  scarring  (sudden  death).  Diphtheritic  con- 
junctivitis occurs  in  about  3  per  cent.  The  skin  is  rarely  the  seat 
of  diphtheritic  inflammation.  Sometimes  diphtheria  pursues  a 
more  chronic  course,  but  is  not  less  dangerous.  The  late  results 
of  the  poison  are  shown  by  various  forms  of  neuritis  and  paralysis. 

The  differentiation  of  true  diphtheria  from  other  pseudo- 
membranous  inflammations  of  mucous  membranes  not  caused 
by  Loffler's  bacillus  is  important.  This  is  especially  true  of  scarlet 
fever,  which  also  goes  along  with  simple  angina  pharyngis  or  diph- 
theritic inflammation  in  the  anatomical  sense.  In  this  instance  the 
pseudo-membrane  appears  more  slimy  and  disconnected,  but  at 
times  may  be  indistinguishable  from  the  diphtheria  by  Ldffler's 
bacillus.  In  some  of  these  cases  Loffler's  bacillus  is  actually  present, 
so  that  we  are  dealing  with  a  combination  of  scarlet  fever  and  diph- 
theria; in  many,  however,  Loffler's  bacillus  is  not  etiologically 
concerned.  This  combination  may  also  occur  in  measles,  erysip- 
elas, etc. 

Finally,  as  in  every  infectious  disease,  it  must  be  remembered 
that,  although  in  general  the  contagiousness  of  diphtheria  is  high, 
the  disease  develops  in  infected  persons  only  on  the  basis  of  a 
specific  disposition  to  this  micro-organism.  Certain  age  periods, 
especially  childhood  and  adolescence,  are  more  susceptible  than 
later  life,  but  even  amongst  individuals  of  the  same  age  disposition 
varies  tremendously  (see  Schick  reaction). 

The  ultimate  solution  of  this  problem  lies  probably  largely  in 
differences  of  anatomical  tissue  organization  and  body  construction. 
Thus,  the  different  organization  of  the  various  age  periods  creates 
differences  in  susceptibility  to  infections  by  changes  in  tissue  soil 
and  environment  which  are  essential  for  anchorage  and  develop- 
ment (biological  affinity)  of  bacteria  (see  more  fully  under 
disposition). 

The  bacteriological  diagnosis  of  the  Loffler  bacillus  must  be 
made  by  culture,  even  if  the  microscopic  examination  of  the  fresh 
spread  shows  characteristic  forms.  For  it  will  presently  be  shown 
that  there  are  strains,  so-called  "diphtheroids,"  which  are  very 


58  GENERAL  PATHOLOGY 

prevalent  in  the  mouth  and  elsewhere,  but  vary  in  cultural  charac- 
teristics and  especially  in  virulence  from  the  Loffler  bacillus.  It  is 
convenient  to  use  for  this  purpose  a  sterile  wire,  the  end  of  which 
is  wrapped  into  absorbent  cotton,  known  as  a  swab.  This  is  carried 
in  a  sterile  tube.  It  is  introduced,  cotton  wrapping  foremost,  into 
the  throat  and  gently  touched  to,  and  moved  over,  the  surface 
of  the  affected  mucous  membrane  (bacilli  are  superficial).  Then 
it  is  withdrawn  and  gently  smeared  over  the  surface  of  several 
slant  serum  tubes  which  are  incubated  for  12  hours.  Colonies  are 
then  visible  on  the  surface  of  the  slant  serum.  These  may  be 
examined  microscopically.  But  even  definite  cultural  results  are  no 
proof  of  the  pathogenicity  of  the  organism.  For  it  has  only  recently 
been  shown  that  there  exist  in  throats  and  wounds  bacilli  which 
morphologically  and  culturally  answer  to  the  Loffler  bacillus, 
but  are  avirulent  (Adami) .  It  is,  therefore,  necessary  to  follow  the 
culture  by  inoculation  into  a  guinea  pig  for  the  characteristic 
anatomical  lesion  and  general  toxic  effects. 

PSEUDO  DIPHTHERIA  BACILLI:  (DIPHTHEROIDS).  In  the  fore- 
going discussion  it  has  been  made  clear  that  the  group  of  the  diph- 
theria bacillus  is  represented,  as  in  other  more  or  less  specific 
bacterial  types,  by  several  members  which  exhibit  differences 
from  the  main  representative  of  the  group,  morphologically, 
culturally  and  pathogenetically.  This  was  already  appreciated  by 
Loffler.  Hofmann  later  studied  one  of  these  forms  which  goes  by 
his  name.  This  organism  is  somewhat  shorter,  thicker  and  stains 
more  homogeneously  with  Neisser  stain.  It  grows  luxuriantly  on 
ordinary  culture  media;  does  not  ferment  sugar,  nor  dextrose  and 
is  non-pathogenic. 

Bacillus  Xerosis.  This  is  a  diphtheroid  which  is  found  in 
conjunctivitis,  but  also  on  the  normal  conjunctiva.  It  resembles 
the  bacillus  of  Loffler  closer  in  morphology  and  cultural  characters 
than  Hofmann's  bacillus,  but  differs  in  behavior  towards  sugar 
media;  it  ferments  sacharose  with  production  of  acid,  while  the 
bacillus  of  Loffler  does  not;  on  the  other  hand,  the  bacillus  xerosis 
does  not  ferment  dextrin  to  acid,  while  Loffler's  bacillus  does.  It 
is,  if  at  all,  weakly  pathogenic. 

The  relation  of  these  diphtheroids,  of  which  there  are  still 


DIPHTHEROIDS  59 

others,  to  the  bacillus  of  Loffler  is  not  clear.  The  fact  that  even  in 
the  true  Loffler  form  pronounced  variations  in  pathogenic  effects 
occur,  so  that  its  mere  discovery  is  no  proof  of  its  infectious  charac- 
ter, makes  the  close  relation  of  all  these  forms  as  modifications 
of  one  type  very  probable.  Diphtheroids  are  of  wide  distribution 
and  their  presence  in  tissues  and  lesions  does  not,  for  reasons 
given  above,  establish  a  necessary  etiological  relationship  to  the 
focus  in  which  they  are  discovered  unless  corroborated  by  animal 
experiment. 

ANTITOXINE.  It  has  been  stated  that  the  investigations  of 
Roux  and  Yersin  demonstrated  that  the  pathogenic  effect  of 
Loffler's  bacillus  lay  mainly  in  a  toxine,  a  poison  dissociable  from 
the  body  of  the  bacilli,  and,  therefore,  an  esotoxine. 

But  it  was  the  merit  of  Behring  with  Kitasato  to  show  that 
inoculation  of  animals  (horses  and  guinea  pigs)  by  repeated 
injection  of  first  attenuated  and  gradually  stronger,  virulent 
bacilli,  rendered  them  resistant  and  that  this  artificial  resistance 
to  the  disease  was  due  to  the  presence  of  a  neutralizing  substance 
or  property  (antibody  to  the  poison)  in  the  blood  of  the  animals 
thus  treated.  In  other  words,  repeated  injection  of  doses  of  the 
poison  too  small  to  be  fatal,  stimulate  the  body  to  the  production 
of  a  neutralizing  substance  which  is  contained  in  its  blood  and 
protects  it  against  further  infection  with  even  virulent  cultures 
or  stronger  poison.  This  antibody  is  contained  in  the  serum,  and  its 
protective  influence  may  be  transferred  through  injection  into 
another  animal.  Injected  after  the  disease  has  developed,  it  aborts 
and  shortens  the  infection. 

The  serum  containing  the  antibody  is  spoken  of  as  antitoxine. 
It  is  important  to  appreciate  here  that  the  antitoxine  is  not  de- 
structive to  the  bacilli  themselves,  but  neutralizes  their  product, 
the  toxine.  We  can  thus  passively  immunize  (protect)  an  animal 
against  this  infection,  or,  once  established,  overcome  or  ameliorate 
it  by  injection  of  the  serum  (antitoxine)  of  another  animal  pre- 
viously immunized.  Thus  antitoxine  immunity  differs,  as  will  be 
shown  in  detail  later,  from  vaccination,  in  which  the  introduction 
of  attenuated  or  dead  bacillary  bodies  actively  stimulates  an 
organism  to  the  formation  of  substances  directed  against  a  later 


60  GENERAL  PATHOLOGY 

infection  with  stronger,  more  virulent  forms,  to  destruction  of 
bacteria  themselves. 

It  is  fortunate  in  this  regard  that  the  bacilli  in  diphtheria  do 
not  penetrate  deeply  and  do  not  invade  throughout  the  whole  body. 
Consequently  neutralization  of  the  poison  is  relatively  more  easily 
accomplished  in  comparison  to  diseases  in  which  bacteria  diffuse, 
grow  and  disintlgrate  throughout  the  body  (Bacteriemia).  Im- 
mediately upon  discovery  of  diphtheria  antitoxine  by  Behring  in 
1893  its  tremendous  practical  importance  was  apparent  and  soon 
established.  Consequently  on  account  of  its  wide  use  and  applica- 
tion as  a  prophylactic  and  curative  measure,  it  became  necessary 
to  find  a  system  of  accurate  measurement  for  dosage.  Here, 
however,  existed  the  apparently  hopeless  difficulty  of  ignorance 
of  the  chemical  or  physical  constitution  of  either  diphtheria  toxine 
or  antitoxine  and  inability  to  isolate  either  in  sufficient  purity  to 
allow  exact  measurement.  Behring  and  Ehrlich,  therefore,  devised 
a  very  ingenious  method  of  calculation  based  on  the  biological 
effects  and  affinity  of  toxine  and  antitoxine.  It  is  possible  by  this 
method  to  establish  accurate  values  of  the  antitoxine  strength  of 
an  immune  serum.  It  is  first  necessary  to  determine  the  strength 
of  the  toxine: 

1 .  As  a  simple  fatal  dose  Ehrlich  regards  that  quantity  of  poison, 
expressed  in  c.c.,  which  kills  a  guinea  pig  of  250  gms.,  in  4  to  5  days. 

2.  A  normal  poison,  according  to  Behring,  is  one  which  contains 
in  i  c.c.  100  fatal  doses  (DTNM250). 

These  arbitrary  values  are  used  for  standardizing  antitoxine, 
as  follows: 

i.  A  simple  serum  is  one  of  which  i  c.c.  exactly  neutralizes 
the  effects  of  i  c.c.  of  normal  poison,  i.e.,  one  hundred  fatal  doses. 

.2.  This  value,  of  i  c.c  of  a  simple  serum,  is  the  antitoxic  unit  or 
unit  of  immunity,  I.  E.,  is  used  as  such  to  express  antitoxine  strength 
or  dosage.  Thus  antitoxine  is  administered  in  antitoxic  units  (usually 
500  to  10,000,  depending  upon  the  purpose).  These  values,  however, 
apply  only  to  the  relationship  of  antitoxine  to  fresh  toxines. 

It  has  been  found  that  if  the  diphtheria  toxine  is  allowed  to 
stand,  its  toxic  property  diminishes,  while  its  ability  to  combine 
with  antitoxine  persists.  Bodies  which  lose  their  toxic  properties 


DIPHTHEROIDS  61 

while  retaining  power  of  combination  with  their  antitoxines  are 
spoken  of  by  Ehrlich  as  toxoids  or  toxones.  To  study  this  peculiar 
phenomenon  quantitatively,  Ehrlich  introduced  two  new  values 
Lo  (zero  limit)  and  L  -f-  (fatal  limit).  Lo  is  the  quantity  of  poison 
+  unit  of  immunity  which  is  completely  physiologically  neutralized 
by  it,  L  -f-  is  the  quantity  of  poison  whch  +  unit  of  immunity  is 
just  sufficient  to  produce  death  in  a  guinea  pig.  This  mixture  con- 
tains, therefore,  a  fatal  dose  in  free  state  and  gives  us  the  toxicity. 
(Lo  -  L  +  =  D  (difference,  fatal  dose). 

In  pure  poisons  D  =  i,  but  in  reality  it  is  generally  higher  on 
account  of  what  Ehrlich  believed  to  be  the  presence  of  toxoids  or 
toxones.  In  older  poisons  L  o  is  lowered.  D  is,  therefore,  the  indica- 
tion (measure)  of  toxone  contents  (weakening)  in  a  poison. 

Scbick  Reaction.  It  has  been  pointed  out  that  infection  with 
Loffler's  bacillus  occurs  only  on  the  basis  of  a  specific  disposition 
to  the  organism.  It  appears  that  certain  persons  possess  normally  a 
sufficient  antitoxic  property  in  their  blood  to  withstand  possible 
infection.  In  order  to  test  the  antitoxic  quality  of  the  blood  and 
thus  save  individuals  the  occasionally  unpleasant  results  of  pro- 
phylactic immunizing  doses  of  antitoxin  (serum  sickness,  anaphy- 
laxis;  see  immunity),  Schick  designed  the  following  reaction. 

An  amount  of  diphtheria  toxine  equivalent  to  J£o  the  minimum 
fatal  dose  for  guinea  pigs,  is  made  up  to  0.2  c.c.  with  sterile  salt 
solution  and  injected  subcutaneously,  or  better,  intracutaneously 
into  the  flexor  surface  of  the  arm.  A  positive  reaction,  signifying 
absence  of  sufficient  antitoxine,  appears  within  24  hours  and  con- 
sists in  swelling  and  diffuse  reddening  of  an  area  of  about  2^  to 
3  cm.  around  the  point  of  injection.  It  fades  within  a  we^k.  If 
the  reaction  is  absent  the  antitoxine  property  of  the  body  may  be 
deemed  sufficient. 

It  has  been  calculated  that  when  the  reaction  is  positive  the 
blood  contains  less  than  %Q  of  antitoxic  unit  per  c.c.,  in  a  faint 
reaction  Y±§  to  J^o  of  antitoxic  unit  per  c.c.  Individuals  giving 
a  negative  reaction  may  be  considered  sufficiently  immune  to 
infection,  but  those  in  which  the  reaction  is  faint  or  definite  should 
receive  immunizing  doses  when  exposed  to  the  danger  of  a  diph- 
theritic infection. 


CHAPTER  XI 

THE  BACILLUS  TUBERCULOSIS 

THE  disease,  or  better  diseases,  which  are  now  collectively  recog- 
nized as  tuberculosis,  have  been  known  for  centuries  under  differ- 
ent names,  especially  as  phthisis.  In  the  writings  of  the  Hindus 
the  disease  is  described.  The  Greeks  already  regarded  the  air  as 
carrier  of  infection  and  the  idea  of  contagiousness  has  persisted 
ever  since.  Morgagni  declared  his  dislike  of  sectioning  tuberculous 
cadavers  for  fear  of  infection. 

The  conception  of  tubercle  (a  nodule)  was  originally,  as  in 
diphtheria,  an  anatomical  one  and  laid  down  by  Sylvius  (1614- 
1672).  Tuberculous  inflammations  were  later  thoroughly  studied 
by  Laennec  and  Virchow.  But  their  etiologic  identity  and  relations 
remained  obscure.  Villemin  (1855)  gave  the  first  experimental 
proof  of  its  infectiousness  by  inoculation  of  tuberculous  material 
into  rabbits.  These  experiments  were  discredited  when  it  was  found 
that  other  foreign  material  produced  similar  nodular  swellings  at 
the  point  of  inoculation.  The  question  was  settled  by  Cohnheim 
in  conclusive  experiments  in  which  he  demonstrated  that  tubercu- 
lous infections  were  not  only  followed  by  local  lesions  at  the  point 
of  inoculation,  but  generalization  from  the  original  focus. 

Even  after  the  infectious  nature  of  tuberculosis  had  thus  been 
established  the  cause  remained  unknown  until  Baumgarten  and 
Koch  (1882)  almost  simultaneously  saw  the  organism  in  tubercu- 
lous material  and  tissues.  Koch's  work  remained  the  more  impor- 
tant on  account  of  its  classic  presentation  and  the  completeness 
with  which  he  traced  the  history  and  characteristics  of  the  bacillus 
through  difficult  cultivation  to  reinfection  in  animals.  By  repeated 
cultivation  (iiooth  generation)  he  obtained  pure  cultures,  and  by 
inoculation  into  monkeys,  rabbits  and  guinea  pigs  regularly 
produced  the  lesions  of  tuberculosis. 

62 


THE  BACILLUS  TUBERCULOSIS  63 

Morphology.  Koch  and  Baumgarten  saw  the  bacillus  first  in 
unstained  tissues  after  clearing  them  in  KOH.  Koch  described 
it  as  a  slender,  short,  non-motile  rod.  Stained,  it  appears  delicate 
with  rounded  extremities,  2  to  4/j  long  (about  %  to  Y±  of  size  of  a 
red  blood  corpuscle)  and  0.3  to  0.5/4  broad.  Frequently  it  is  slightly 
curved. 

The  bacilli  are  found  isolated  or  in  small  groups  lying  across 
each  other.  In  tissues  they  are  generally  in  cells.  Spore  formation 
is  still  questionable.  Some  points  are  in  favor  of  it.  It  is  also  stated 
that  the  bacilli  show  at  times  nuclear  contents.  Characteristic  is 
pleomorphism,  i.e.,  great  variation  in  form,  shape  and  arrangement. 
Bacilli  appear  in  certain  strains,  long,  thick,  filamentous  or  linked 
to  threads,  branches,  forks;  in  others  they  are  short,  thin  or  thick, 
isolated  rods.  They  approach,  therefore,  a  higher  botanical  order 
and  are  related  to  actinomyces  and  the  hyphomyces. 

Staining  Properties.  To  demonstrate  the  bacilli,  solid,  grayish 
particles  of  tuberculous  sputum  or  tuberculous  pus  are  well  suited. 
These  are  thinly  spread  on  a  cover  glass  or  slide  with  a  platinum 
needle,  dried  and  fixed  by  passing  them  through  a  flame  rapidly 
about  three  times,  or  gently  waving  them  over  the  flame  to  coagu- 
lating temperature. 

If  the  suspected  material  is  very  thick  and  tenacious  or  con- 
taminated with  other  bacteria,  it  is  well  to  emulsify  it  with  a 
solution  of  potassium  hydrate.  For  this  purpose  antiformin1  is 
used.  This  solution  destroys  organic  substances  through  liberation 
of  chlorine,  but  leaves  intact  acid-fast  bacilli,  on  account  of  their 
waxy  capsule. 

The  suspected  material  is  therefore  mixed  with  25  to  50  per 
cent,  of  antiformin  in  a  tube  (depending  upon  thickness  of  ma- 
terial) and  well  shaken  until  all  solid  matter  is  thoroughly  disin- 
tegrated and  the  contents  appear  as  a  turbid,  homogeneous  fluid. 
The  disintegration  is  hastened  by  incubation  for  30  minutes  at 
37°C.  The  fluid  is  then  centrifugalized  at  high  speed.  The  super- 
natant fluid  is  pipetted  off,  the  test  tube  filled  with  sterile  water  and 
again  centrifugalized.  This  is  repeated.  The  sediment  is  injected 

1  Antiformin  has  nothing  to  do  with  formalin,  but  consists  in  equal  parts 
of  liquor  sodii  chloratis  and  sodium  hydrate. 


64  GENERAL  PATHOLOGY 

into  guinea  pigs  for  development  of  tuberculous  lesions.  If  only 
microscopic  slides  are  to  be  prepared,  shake  with  petroleum  ether, 
or  chloroform,  centrifugalize,  and  then  prepare  the  slide  film  from 
the  surface  of  the  fluid  if  petroleum  ether  is  used,  and  from  the 
bottom  if  chloroform  is  used.  In  films  thus  prepared  the  tubercle 
bacilli  are  demonstrated  by  a  specific  staining  quality  which  they 
have  in  common  with  some  other  bacteria.  This  depends  upon 
the  fact  that  the  bacilli,  although  taking  aniline  stains  with  diffi- 
culty, discharge  the  stain  with  equal  difficulty  when  treated  with 
acids  and  alcohol.  They  are,  therefore,  spoken  of  as  acid-fast. 
This  quality  depends  upon  the  presence  of  a  waxy  capsule. 

The  method  consists,  therefore,  in  overstaining  in  an  aniline 
dye  (preferably  acid  fuchsin)  and  then  decolorizing  with  a  dilute 
mineral  acid  and  alcohol.  In  this  way  other  bacteria  discharge 
the  stain,  while  tubercle  bacilli  retain  it.  The  stain  employed 
for  this  purpose  in  ZiehPs  solution  of  i  gr.  fuchsin,  dissolved  in 
10  c.c.  absolute  alcohol  and  90  c.c.  5  per  cent,  carbolic  acid.  The 
latter  acts  as  a  mordant  and  keeps  the  solution  durable.  An  excess 
of  the  solution  is  placed  on  the  fresh  film  and  the  slide  heated  to 
just  within  the  boiling  point,  and  kept  steaming,  but  not  boiling 
for  a  few  minutes.  The  stain  is  then  poured  off  and,  without 
washing  in  H2O,  the  film  is  thoroughly  decolorized  by  alternate 
immersion  in  a  25  per  cent,  solution  of  a  mineral  acid  and  absolute 
alcohol,  until  all  stain  is  apparently  extracted.  Then  wash  in 
H2O.  Counter-stain  in  methylene  blue,  wash  in  H2O,  dry  and  mount. 
Examine  with  oil  immersion. 

Shorter  and  more  condensed  methods  have  been  recommended, 
such  as  Gabbet's  (see  books  on  bacteriological  technique),  but 
they  are  neither  so  exact  nor  so  reliable  as  carefully  conducted, 
consecutive  steps  of  procedure. 

It  has  been  pointed  out  and  emphasized  by  Much  that  not  all 
tubercle  bacilli  are  acid-fast.  Certain  forms  and  phases  of  develop- 
ment, especially  of  the  bovine  type,  lack  the  acid-fast  property. 
They  may  subsequently  become  acid-fast  in  culture. 

Cultivation. — The  tubercle  bacillus  is  cultivated  with  difficulty, 
owing  to  its  slow  development  and  consequent  easy  overgrowth 
by  other  bacteria.  Koch  finally  succeeded  by  employing  solid 


THE  BACILLUS  TUBERCULOSIS  65 

blood  serum.  Not  until  the  4th  and  5th  day  may  delicate  points  be 
recognized  with  the  magnifying  glass.  They  grow  very  gradually 
to  the  fourth  week. 

It  was  later  found  that  glycerine  cultures  with  acid  reaction  are 
better  adapted  than  pure  serum. 

Subsequently  Hesse  introduced  a  much  employed  useful  medium 
consisting  of  nutrose  10  gm.,  sod.  chlor.  5.0  gm.,  glycerine  30  gm., 
normal  sol.  of  cryst.  soda  (28.6  per  cent).  5  c.c.,  H2O  1000  c.c.  On 
this  pure  cultures  grow  in  about  4  to  5  days  in  loops  and  pigtail 
fashion.  More  recently  Dorset's  egg  medium  and  Smith's  dog 
serum  have  been  employed  in  cultivation  from  tissues  directly. 

The  tubercle  bacillus  requires  much  air  for  its  growth  and  it  is 
susceptible  to  temperature.  The  human  type  does  not  grow  at 
temperatures  over  42°C.  or  below  3O°G;  only  the  avian  type 
endures  somewhat  higher  temperatures.  Other  outside  influences 
are  better  tolerated.  It  is  resistant  to  drying  for  several  months 
(three),  also  to  cold  and  heat.  Thus  a  temperature  of  ioo°C.  is 
tolerated  for  one  hour.  But  steam  kills  it  in  about  30  minutes  and 
boiling  in  five  minutes.  In  beef  it  persists  unless  thoroughly 
cooked.  Rare  beef  still  contains  viable  bacilli. 

Disinfection  of  tuberculous  material,  such  as  sputum,  is  best 
accomplished  by  sulphurous  acid  or  formalin,  not  by  bichloride 
of  mercury  or  other  precipitants  of  albumen  which,  on  account 
of  their  precipitating  quality  do  not  sufficiently  penetrate.  A  five 
per  cent,  carbolic  acid  solution  kills  in  about  24  hours;  absolute 
alcohol  in  about  ten  hours. 

Pathogenic  Effects.  These  are  first,  local;  secondly,  general. 
They  are  the  results  of  the  irritating  influence  of  the  bacilli  and 
their  toxine  which  appears  to  be  derived  from  the  destruction 
of  the  bacillary  body  and  not  well  separable  from  it.  It  is, 
therefore,  an  endotoxin.  The  local  manifestations  consist  of  the 
tubercle,  a  nodular  granulomatous  inflammation,  caused  by  pro- 
liferation of  fixed,  endothelial  and  connective  tissue,  cells  mixed 
with,  and  surrounded  by,  lymphocytes  (granuloma).  Character- 
istic is  the  presence  of  giant  cells  and,  more  especially,  the 
tendency  to  complete  necrosis  and  cheesy  disintegration  of  the 
tubercle  and  the  tissue  in  which  it  is  seated.  This  is  the  result  of 

5 


66  GENERAL  PATHOLOGY 

the  toxines  liberated  from  the  disintegrating  bodies  of  the  bacilli 
and  it  varies  in  different  strains  in  quantity,  and  possibly 
quality,  so  that  the  extent  and  degree  of  the  so-called  "caseation" 
of  the  tissues  vary  in  different  tuberculous  infections.  The  same 
is  true  of  the  exudative  processes  which  surround  the  tubercle. 
Secondary  infections,  especially  with  streptococci,  acquire  great 
importance;  they  follow  close  upon  the  path  of  the  tubercle 
bacilli  (see  under  Infective  Granulomata,  page  236). 

Paths  of  Injection.  This  is  still  a  much  discussed  question. 
Tubercle  bacilli  may  reach  an  organ  through  the  blood  and  lymph 
stream,  especially  the  latter.  Aerogenous  infection  of  the  lungs, 
that  is  due  to  direct  inhalation,  was  formerly  believed  to  be  a  very 
common  method  of  introduction.  Recently,  however,  it  has  be- 
come very  doubtful  whether  it  ever  occurs,  because  the  anatomical 
distribution,  formerly  thought  to  be  characteristic  of  aerogenous 
infection,  is  closely  simulated  and  reproduced  by  lymphatic  infec- 
tion and  extension. 

Generally  speaking  the  tubercle  bacillus  produces  a  nodule  at  the 
point  of  entrance  and  then  creeps  along  lymph  channels  to  the 
regionary  glands  which  it  involves.  Tuberculous  infection  may 
occur,  however,  without  leaving  a  trace  at  its  port  of  entrance  (for 
instance  through  the  mucous  membrane  of  gastro-intestinal  tract 
or  skin)  and  it  may  even  pass  glands,  before  its  final  lodgment. 
This  makes  it  difficult  and  at  times  impossible  to  determine  in  a 
given  case  the  mode  and  path  of  infection. 

There  is  not  an  organ  which  is  immune  to  tuberculosis.  Skin, 
digestive  apparatus,  respiratory  tract,  bones,  joints,  serous  mem- 
branes, brain  and  spine  and  cord,  ductless  glands  and  even  the 
organs  of  the  special  senses  may  be  primarily  or  secondarily  in- 
volved. Frequently  the  primary  focus  may  remain  small  and  rela- 
tively unimportant,  but  may  give  rise  to  a  serious  fatal,  consequent 
infection,  such  as  tuberculous  meningitis  following  upon  tubercu- 
losis of  bones  or  joints,  etc. 

The  pathogenic  importance  of  the  acid-fast  waxy  capsule  of  the 
tubercle  bacillus  has  attracted  much  attention,  especially  since 
it  is  known  that  the  bacillus  is  not  always  acid-fast.  Theobald 
Smith  has  advanced  the  hypothesis  that  the  capsule  is  really  a 


THE  BACILLUS  TUBERCULOSIS  67 

protection  to  the  bacillus  and  that  it  remains  attached  to  the  or- 
ganism until  this  finds  a  suitable  soil  for  growth.  Then  it  is  re- 
moved by  solvent  action  of  fluids,  and  the  organism  becomes  active. 
Thus  it  happens  that  young  tubercle  bacilli  are,  as  Much  pointed 
out,  usually  not  acid-fast.  If  this  hypothesis  is  correct,  it  would 
explain  the  latency  of  certain  tuberculous  infections.  The  neces- 
sary lipase  for  the  solution  of  the  capsule  is  supposed  to  be  derived 
from  lymphocytes  and  mononuclear  leucocytes  and  certain 
parenchyma  cells  which  are  apparently  rich  in  it. 

The  tubercle  bacillus  exists  in  several  group  types  and  it  is  pos- 
sible, besides  the  type  mostly  found  in  human  beings,  to  distinguish 
three  types  of  practical  interest,  the  avian,  the  bovine,  and  a  form 
occurring  in  cold-blooded  animals. 

The  Avian  Type.  This  is  closely  related  to  the  human  type. 
It  occurs  in  hens,  pheasants,  pigeons,  turkeys,  wild  ducks  and 
geese.  In  an  investigation  of  600  chickens,  62  were  found  tubercu- 
lous. Koch  first  regarded  it  as  identical  with  the  human  form,  but 
differences  were  found.  It  grows  at  higher  temperatures,  45  to  5O°C. 
and  does  not  readily  affect  rabbits  and  guinea  pigs,  and  it  is  also 
more  easily  cultivated.  Some  birds,  like  the  parrot,  are  susceptible 
to  both  avian  and  human  tuberculosis.  Other  animals  show  varying 
behavior  towards  both  forms.  In  man  infection  is  practically 
unknown,  it  having  been  observed  only  in  very  few  instances. 

The  Bovine  Type  (Perlsucht).  This  type  is  the  cause  of  tuber- 
culosis in  cattle,  and  also  infects  sheep,  pigs  and  goats.  Its  mani- 
festations are  coarser,  gross,  nodular,  and  with  predilection  affect 
serous  membranes.  The  tendency  to  caseation  and  cavity  formation 
is  less  than  in  the  human  type.  Morphologically  and  culturally  the 
differences  are  extremely  slight.  Acid  glycerine  broth  is  rendered 
gradually  alkaline  by  the  bovine  type. 

The  question  of  the  possibility  of  human  infection  by  the  bovine 
form  has  been  actively  discussed  without  as  yet  full  agreement. 
Koch  admitted  the  possibility,  particularly  in  early  life,  but  denied 
its  general  importance  in  man,  as  compared  to  infection  with  the 
human  type.  It  is  also  held  by  some  that  many  milk  infections  are 
really  due  to  contamination  with  human  tubercle  bacilli.  On  the 
other  hand  others  strongly  contend  that  the  bovine  type  is  patho- 


68  GENERAL  PATHOLOGY 

genie  to  man,  that  it  plays  a  large  role  in  the  glandular  tuberculosis 
of  children,  and  that  it  may  also  be  recovered  in  a  certain  number 
of  genuine  cases  of  tuberculosis  of  adults.  Investigations  by 
Weber  of  628  cases  which  covered  284  children,  335  adults  and 
9  of  unstated  age,  all  of  whom  had  been  exposed  to  the  effects  of 
milk  from  cows  with  tuberculous  udder,  showed  that  only  two  very 
young  children  had  apparently  been  infected  with  the  bovine 
type. 

The  exact  observations  of  Park  and  Krummwiede  make  it 
appear  that  bovine  infection  is  relatively  common  in  youth  to  16 
years,  but  uncommon  in  adults.  The  matter  needs  still  further 
investigation,  especially  in  view  of  the  history  of  some  of  these 
apparent  bovine  infections  in  youth,  which  in  later  life  present  the 
characteristics  of  human  infection.  Are  these  independent  occur- 
rences or  in  any  way  related?  Do  tubercle  bacilli  change  in  charac- 
teristics in  different  animal  environment?  These  are  still  unsolved 
questions. 

Tuberculosis  of  Cold-Blooded  Animals.  Tuberculosis  occurs  in 
carp,  lizards,  snakes,  and  turtles,  and  seems  to  be  insignificant 
in  relation  to  human  infection. 

IMMUNIZATION.  Koch  attempted  to  establish  an  immunity 
against  tuberculosis;  but  this  is  a  different  and  in  a  way  more 
difficult  problem  than  in  diphtheria. 

We  have  already  seen  that  the  tubercle  bacillus  does  not  produce 
a  definitely  recognizable  toxine  which,  as  in  the  case  of  the  LofHer 
bacillus,  diffuses  easily  through  the  body.  The  tuberculous  toxine 
is  not  easily  separated  and  widely  disseminated  from  the  bacillary 
bodies,  but  seems  to  be  generated  by  their  disintegration  and  in 
varying  amounts  and  quality  in  different  strains.  Its  effects  are 
local,  or  at  least  close  to  its  origin  (Cheesy  pneumonia).  Moreover 
almost  all  cases  of  well-established  tuberculous  infection  are  mixed 
infections.  We  have  already  seen  that  streptococci  are  responsible 
for  much  of  the  secondary  and  late  manifestations  connected  with 
the  breaking  down,  fusion  and  cavitation  of  the  infected  tissues. 

Koch  endeavored  to  induce  immunity  by  making  a  glycerine, 
extract  of  dead  tubercle  bacilli  and  injecting  it.  It  was  his  effort 
to  stimulate  the  body  to  greater  reaction  against  the  tuberculous 


THE  BACILLUS  TUBERCULOSIS  69 

infection,  that  is,  the  bacteria  themselves.  This  was  tuberculin.  Its 
office  was  to  be  active  immunization  of  an  individual,  contrasted 
to  the  passive  neutralizing  action  of  diphtheria  antitoxine.  For 
the  reasons  given  above,  the  results  were  not  uniformly  satis- 
factory and,  of  course,  useless  in  active  general  and  advanced 
tuberculous  infections  in  which  the  body  is  already  overloaded 
with  all  sorts  of  dead  bacilli.  It  is,  however,  suited  for  localized, 
chronic,  slowly  progressing  tuberculous  infections,  especially  of 
the  glandular,  bone,  joint  and  skin  type,  and  in  children.  The  dose 
has  to  be  carefully  adjusted.  McKenty  found  the  best  results  with 
bacillus  emulsion  in  doses  of  from  ;H}0»ooo  mg.  to  Hooo  mg.  in 
children  and  Ko.ooo  mg.  to  Ksoo  mg-  m  adults. 

Tuberculin  is  now  extensively  employed  for  diagnostic  purposes. 

(1)  Intravenously.  The  old  tuberculin  of  Koch  in  doses  of  o.i  to 
0.2  mg.  is  followed,  in  positive  reaction,  by  rise  of  temperature  in 
from  12  to  48  hours,  at  least  J^°  over  the  previous;  constitutional 
effects,  accentuation  of  T.B.C.  symptoms,  swelling  of  glands,  etc. 

(2)  Ophtbalmo.  Tuberculin  reaction  of  Wolff- Eisner  and  Calmette. 
Apply  drop  of  tuberculin  to  conjunctiva.   In  positive  reaction 
followed  by  sharp  congestion.  (3)  von  Pirquet's  cutaneous  reaction. 
Solution  made  up  of  25  per  cent,  old  tuberculin  in  salt  solution 
and  carbolic  acid.  Place  2  drops  on  skin  and  scarify.  After  24  to  48 
hours  in  tuberculous  patients  small  papules  and  vesicles  appear. 
This,  however,  is  not  always  an  indication  of  active  tuberculous 
lesions  and,  especially  in  adults,  may  be  due  to  an  old,  latent  focus. 

OTHER  ACID-FAST  BACILLI.  Smegma  bacillus  occurs  in  preputial 
and  vaginal  secretion.  Morphologically  it  resembles  the  tubercle 
bacillus  closely,  but  is  much  less  resistant  to  the  action  of  acid  and 
alcohol.  It  is  apt  to  occur  in  urine  and  feces  and  give  rise  to  diagnos- 
tic error.  This  can  be  excluded  by  prolonged  decolorization  with 
absolute  alcohol  after  acid,  overnight  or  at  least  1 2  hours. 

Butter  bacilli  are  also  somewhat  similar  to  the  tubercle  bacillus, 
but  also  less  acid-fast. 

Timothy  or  bay  bacillus  is  found  in  hay  infusions  (grass  bacillus) 
is  even  more  easily  decolorized  by  hot  water.  In  all  doubtful 
cases  animal  inoculation  (guinea  pig)  is  necessary. 


CHAPTER  XII 

THE  BACILLUS  OF  LEPROSY 

LEPROSY  is  a  very  ancient  disease,  known  to  the  Egyptians  and 
Greeks  many  centuries  before  Christ.  It  was  early  transported  to 
Italy  and  the  rest  of  Europe.  Leprosy  hospitals  were  established 
in  A.  D.  636  in  Italy,  France  and  Belgium.  In  757  and  789  Charle- 
magne made  it  a  cause  for  divorce  and  declared  such  marriages 
unlawful.  Leprous  patients  were  considered  dead  and  a  requiem 
mass  was  celebrated  on  their  entrance  to  a  hospital.  During  the 
Crusades  the  disease  became  even  more  prevalent,  as  many  con- 
tracted the  disease  in  the  Orient.  In  1229  there  were  in  France  2000 
leper  hospitals  and  19,000  in  the  whole  of  Europe.  In  England  the 
first  hospital  was  put  up  in  A.D.  1 100,  but  the  disease  was  already 
known  in  the  tenth  century  in  Wales.  Later,  1 1 2  leprosy  houses 
were  founded  in  England.  In  Norway  the  disease  was  recognized 
in  the  thirteenth  century  and  from  Germany  it  spread  to  Denmark, 
Sweden  and  Finland.  To-day  the  disease  has  almost  disappeared 
except  in  Spain,  Italy,  Russia,  Finland  and  Sweden.  It  is  still 
relatively  frequent  in  Norway  and  Iceland.  Foci  exist  in  South 
America,  China  and  Africa;  in  India  the  number  of  lepers  is  esti- 
mated at  100,000,  in  Japan  40,000.  In  the  United  States  were 
reported  150  cases  in  1909  as  against  278  in  1902,  mostly  in 
Louisiana,  and  750  in  the  Hawaiian  Islands.  It  is  endemic  still  in 
the  Philippines  and  Sandwich  Islands. 

Morphology.  The  bacillus  of  leprosy  was  discovered  by  Hansen 
of  Norway,  in  1872,  in  characteristic  round  or  oval  clear  cells  of 
the  leprous  granuloma.  It  is  a  small  rod  of  6/i  which  in  staining 
qualities  closely  resembles  the  tubercle  bacillus.  The  leprous  lesions 
resemble  the  tuberculous  nodule,  but  they  lack  the  characteristic 
caseation  and  display  greater  tendency  to  scar  tissue  formation. 
The  bacilli  are  often  present  in  the  leprous  tubercle  in  enormous 
numbers  and  lie  mostly  intracellular. 

70 


THE  BACILLUS  OF  LEPROSY  71 

Cultivation  and  Inoculation.  Recent  investigators  have  claimed 
cultivation  and  inoculation  (Duval,  Clegg)  but  these  are  doubtful. 
The  bacilli  are  supposed  to  develop  in  the  presence  of  other  bacteria 
which  possess  the  ability  to  split  albumen  into  amino-acids  or  in 
the  presence  of  tryptic  enzymes.  It  is  also  held  by  these  investiga- 
tors that  the  disease  can  be  reproduced  in  monkeys  and  rats. 

Patbogenesis.  Two  forms  of  leprosy  are  known  in  man,  the 
nodular  and  anesthetic.  The  first  occurs  in  tumor-like,  deforming 
growths  over  the  whole  skin  and  also  the  larynx,  and  slowly  leads 
to  death  (lepra  tuberosa).  The  second  is  merely  an  anesthetic 
neuritis  with  erythematous  discoloration  of  the  skin.  The  two  forms 
may  combine.  How  infection  occurs  is  not  known.  The  idea  of  fish 
infection  is  now  abandoned.  Nurses  and  physicians  in  contact  with 
leprous  patients  are  rarely  infected.  Flies  have  been  held  as  carriers. 
The  disease  shows,  besides  external  manifestations,  the  result  of 
general  infection  in  fever  attacks  and  leprous  nodules  in  spleen, 
kidney  and  other  parenchymatous  organs;  also  on  the  mucous 
membranes  of  the  mouth,  throat,  nose  and  larynx.  One  case  which 
I  saw  autopsied  on  Blackwell's  Island,  New  York,  died  after 
years  of  laryngeal  involvement.  Saliva  and  nasal  secretions  contain 
bacilli.  The  disease  is,  in  the  temperate  climates  at  least,  very 
slowly  but  persistently  progressive,  lasting  decades. 


CHAPTER  XIII 
ACTINOMYCOSIS 

ACTINOMYCOSIS  is  a  specific,  purulent  and  granulomatous  infec- 
tious disease  of  animals  and  man,  caused  by  the  ray  fungus.  It 
was  discovered  in  carious  bones  of  the  spine  and  jaw  and  in  the 
tongue.  Bellinger,  in  1877,  properly  recognized  and  described  it  in 
cattle.  Harz  defined  its  botanical  position.  The  name  is  derived 
from  axrts  (ray)  and  nvKrjs  (fungus).  Ponfick  identified  the  disease 
in  man  and  cattle,  and  Johne,  in  1882,  traced  it  to  tonsilar  infection. 

As  the  name  implies,  actinomyces  belongs  to  the  filamentous 
fungi,  is  closely  related  to  the  hyphomyces  or  molds,  and,  there- 
fore of  a  higher  botanical  order  than  bacteria  proper  (Schizomy- 
ces).  It  belongs  to  the  order  of  trychomyds,  (0pt£  =  hair),  or 
streptothrix  group,  all  of  which  are  delicate  filamentous  branching 
or  pseudo-branching  organisms.  Very  near  to  these  stand  the 
tubercle,  leprosy  and  glanders  bacilli  which  at  times  also  exhibit 
tendency  to  filamentous  growth. 

The  recognition  of  actinomyces  is  relatively  easy;  the  purulent 
detritus  in  this  infection  contains  fine  rice  granule-like  particles 
which  are  largely  composed  of  colonies  of  the  fungus.  These  gran- 
ules are  o.ooi  to  0.2  mm.  and  even  to  0.75  mm.  large,  and  are 
grossly  easily  visible.  Examination  under  the  microscope  discloses 
a  characteristic  radiating  arrangement  of  the  hyphens  (hence  the 
name).  The  hyphens  carry  at  their  ends  long,  club-shaped,  bright 
cells,  while  in  the  center  they  exhibit  a  diffuse,  filamentous  inter- 
woven network.  The  admixture  of  other  cell  and  purulent  detritus 
sometimes  obscures  this  picture,  but  the  addition  of  30  per  cent. 
NaOH  clears  the  field.  The  club-shaped  filaments  are  of  gelatinous 
consistency.  The  nature  of  the  clubs  have  been  an  object  for  discus- 
sion. Originally  held  to  be  spores,  they  are  now  considered  to  be 
involution  forms  and  depend  for  their  formation  on  a  gradual 
inhibition  in  growth  of  the  filaments  which  leads  to  a  gelatinous 

72 


ACTINOMYCOSIS  73 

expansion  of  the  extremity.  The  size  and  arrangement  of  the  fila- 
ments vary.  They  are  always  more  or  less  wavy,  somewhat  spirillar 
and  the  fungus  sheath  may  contain  small  cocci-like  granules. 
They  exhibit  true  branching.  Coccoid  central  borders  have  been 
regarded  as  spores,  but  this  is  recently  denied  (Jordan).  The  older 
the  colonies,  the  more  convoluted  their  center,  while  the  filaments 
at  the  periphery  are  long  and  extend  by  characteristic  radiation. 
The  club-shaped  extremities  do  not  make  their  appearance  until 
late  and  the  gradual  formation  of  the  clubs  in  different  filaments 
may  be  noted. 

Culture.  Culture  is  made  with  difficulty,  but  may  be  done  on 
gelatine,  agar,  glycerine  agar,  potato  and  watery  egg  solution.  The 
organism  is  a  facultative  anaerobe  and  resistant  to  drying  (over 
one  year).  It  is,  however,  susceptible  to  temperature,  being  killed 
at  6o°C.,  more  readily  at  75  to  8o°C.  On  the  other  hand,  it  stands 
sunlight  well. 

Method  of  Injection.  In  cattle  and  pigs  the  infection  occurs 
mostly  from  contaminated  grass  and  grain,  especially  when  feeding 
in  swampy  districts  and  in  wet  years  when  cattle  are  fed  on  barley 
coming  from  flooded  districts.  Thus  Johne  found  in  1882  that  the 
tonsils  of  pigs  contained  barley  grain  studded  with  active  mycotic 
granules.  Bostrom  found  such  grains  in  the  gums  of  actinomycotic 
cattle.  They  may  also  occur  in  corn  and  other  grain  and  hay, 
maize  and  straw.  Direct  communication  from  barley  or  ears  of 
corn  to  man  has  been  demonstrated  through  swallowing  or  chewing 
of  grain  stalks.  While  the  infection  occurs  mostly  through  the 
tonsils  or  carious  teeth,  it  is  also  possible  through  the  intestinal 
tract. 

Pathogenicity.  Actinomycotic  lesions  of  the  bones  of  the  jaw  are 
frequent  in  cattle.  For  this  reason  the  disease  has  long  been  popu- 
larly named  "lumpy  jaw."  The  involvement  of  the  jaw  is  less 
frequent  in  man.  It  produces  tumor-like  swellings,  which  break 
down,  and  undergo  purulent  softening  with  destruction  of  the 
bone.  The  ray  fungus  grows  into  the  soft  tissue  through  the  mucous 
membrane  of  the  mouth,  leads  to  the  formation  of  nodular  inflam- 
matory masses  with  necrosis  and  a  purulent  peripheral  mantle. 
A  localizing  scar  formation  occurs  around  such  areas.  But  while 


74  GENERAL  PATHOLOGY 

cicatrizing  in  one  part  it  progresses  to  another  and  produces 
secondary  actinomycotic  inflammations  in  heart,  kidneys,  brain, 
etc.  Characteristic  is  its  progress  by  fistulous  canals  with  tendency 
to  break  through  to  the  surface,  especially  through  the  skin. 

In  man  secondary  involvement  of  lung,  appendix,  and  diaphragm 
is  not  infrequent. 

A  closely  related  type  of  organism  is  found  in  Madura  foot. 

Various  other  members  of  the  streptothrix  or  nocardia  (Nocard, 
French  veterinarian)  group  possess  pathogenic  interest.  These  are 
practically  important,  because  their  lesions  are,  especially  in  the 
lung,  very  similar  to  tuberculosis.  They  are  widely  distributed 
in  soil,  water  and  foodstuffs.  Morphologically  they  are  pleiomor- 
phous,  short  or  long,  thick  rods  or  coccoid  bodies  or  branching  long 
filaments  (mycelia).  They  do  not  form  radiating  clusters  as  actino- 
myces  do.  A  member  of  this  group  is  cladothrix,  another  try- 
chomyces,  which  exhibits  only  pseudo-branching  and  is  generally 
non-pathogenic.  Crowdy  has,  however,  described  one  case  of  a  pro- 
bable enteric  infection  and  indolent  ulceration  in  a  debilitated 
subject. 

True  molds  (mucor-corymbifer,  aspergillus;  sporothrix)  are 
rarely,  but  occasionally  concerned  in  pulmonary  infections,  indo- 
lent gastrointestinal  ulcerations  and  skin  affections.  They  simu- 
late tuberculosis. 

Blastomycosis.  Pathogenic  yeasts  have  recently  been  brought 
into  prominence.  Generally,  yeasts  are  harmless  saprophytes. 
They  are  round  ovoid,  sometimes  capsulated  cells  with  bright 
eccentric  granules  which  propagate  by  budding.  They  occur  in  the 
stomach  and  gut,  where  they  ferment  carbohydrates.  There  have 
been  described  granulomatous,  ulcerative  and  purulent  inflamma- 
tions of  the  skin,  lungs  and  glands  in  which  pathogenic  yeasts 
appear  to  be  the  cause  and  can  be  demonstrated  in  the  inflamma- 
tory lesions. 


CHAPTER  XIV 
BACILLUS  MALLEI  (GLANDERS) 

GLANDERS  is  a  disease  of  horses  which  can,  however,  be  trans- 
mitted to  man.  It  is  a  dangerous,  easily  transmittible  disease 
which,  while  long  recognized,  was  not  accurately  known  until  the 
nineteenth  century,  when  Rayer  injected  horses  with  material 
obtained  from  human  glanders.  The  cause  of  glanders,  the  bacillus 
mallei,  was  discovered  by  Loffler  and  Schiitz  in  1882  and  the  disease 
fully  described  by  Loffler  in  1886. 

The  disease  runs  an  acute  or  chronic  course  which  easily  merges 
one  into  the  other.  In  the  acute  forms  the  horses  develop  a  high 
fever,  chills  and  great  prostration.  The  mucous  membranes  are 
early  injected  and  reddened.  After  one  to  three  days  appear  the 
local  manifestations  on  the  mucous  membrane  of  the  nose,  ec- 
chymoses,  confluent  nodules  and  pustules  which  rupture  and  dis- 
charge a  seropurulent  fluid.  The  mucous  membrane  then  ulcerates 
and  the  lesion  extends  to  the  larynx  (difficult,  sterterous breathing). 
Skin  lesions  appear  as  pustules.  The  lymph  glands  are  enlarged. 
The  name  farcy  applies  to  cases  in  which  lymphatics  thicken  and 
form  farcy  buds.  Death  occurs  in  from  8  to  30  days  from  asphyxia 
and  intoxication. 

The  chronic  infection  is  much  more  frequent  (90  per  cent.).  It 
develops  insidiously,  slowly  and  may  last  for  months  or  years. 
The  lesions  and  symptoms  are  less  pronounced  and  less  active  and 
the  skin  or  nasal  manifestations  are  most  prominent.  In  man 
glanders  in  very  similar  and  involves  all  viscera. 

The  bacillus  is  a  small  rod,  straight  or  slightly  curved,  of  about 
the  same  length  as  the  tubercle  bacillus,  but  shorter  and  thicker. 
It  is  non-motile,  forms  no  spores,  but  is  apt  to  stain  irregularly. 
Larger  filaments  with  swollen  ends  and  branching  forms  have  been 
observed.  It  stains  with  the  ordinary  dyes,  especially  when  con- 
taining alkalis  or  carbolic  acid,  which  act  as  mordant.  It  is  Gram 
negative  and  decolorized  by  alcohol. 

75 


76  GENERAL  PATHOLOGY 

Cultures.  Cultures  may  be  made  on  ordinary  media,  particu- 
larly in  the  presence  of  glycerine.  The  growth  on  potato  is 
rather  characteristic;  it  is  tenacious,  from  light  to  dark  brown 
color  and  honey-like.  Cultures  are  easily  destroyed. 

Patbogenicity.  The  micro-organism  is  pathogenic  to  all  car- 
nivora,  horse  and  man,  while  cattle  and  the  house  rat  are  immune. 
The  port  of  entrance  is  probably  through  erosions  in  the  mucous 
membrane. 

The  bacteriological  diagnosis  of  glanders  infection,  which  is  often 
important,  is  made  by  inoculation  of  the  material  into  a  guinea  pig, 
by  the  so-called  mallein  test,  and  by  agglutination.  The  character- 
istic lesion  of  the  glanders  bacillus  in  the  guinea  pig  is  orchitis  with 
marked  testicular  swelling.  This  is  followed  by  general  infection 
and  pyemia.  The  value  of  this  test,  however,  is  not  absolute.  It 
must,  therefore,  be  supplemented  by  the  other  two:  The  mallein 
test  consists  in  the  injection  of  mallein  (glycerine)  broth  of  dead 
glanders  bacilli  (prepared  after  the  fashion  or  tuberculin)  into  the 
suspected  animals.  In  glanders  occurs  rise  in  temperature  (increase 
of  from  1.5°  to  2.5°C.),  pronounced  local  swelling  at  the  point  of 
injection,  and  constitutional  symptoms.  Agglutination  is  performed 
in  infected  animals  in  dilutions  of  one  to  3200;  1:500  is  still  un- 
certain. Serum  of  normal  horses  agglutinates  to  1 :2oo. 


CHAPTER  XV 
ANTHRAX 

ANTHRAX,  splenic  fever,  wool-sorter's  disease,  or  malignant  pus- 
tule, is  a  disease  which  affects  with  equal  virulence  all  higher  verte- 
brates and  man.  Since  olden  times  it  has  been  prevalent,  destruc- 
tive to  agriculture  and  dangerous  to  certain  trades  which  come  in 
contact  with  animals  or  parts  of  animals  subject  to  the  disease. 
The  disease  played  an  important  part  in  Rome.  Ovidius  and  Seneca 
mention  it  and  two  Roman  Consuls,  Rufus  and  Bassus,  are  said  to 
have  died  of  it.  From  Middle  Ages  to  modern  times  serious  epidemic 
outbreaks  have  from  time  to  time  taken  place  and  destroyed  ani- 
mals and  man.  A  restraint  and  prevention  of  the  disease  became 
possible  after  Koch  had  fully  described  the  causative  micro-organ- 
ism and  its  methods  of  growth  and  infection.  In  Russia  the'disease 
is  known  as  Siberian  Pest. 

Anthrax  seems  to  be  bound,  more  or  less,  to  certain  localities; 
swampy  moors,  turfy  ground  and  wet  soils,  are  particularly  favor- 
able to  it,  especially  when  in  heated  condition,  as,  for  instance, 
drying  swamps  or  moist  ground  immediately  after  a  draught.  The 
disease  is,  therefore,  more  liable  to  occur  in  early  spring  or  autumn. 
It  affects  the  majority  of  domestic  and  wild  animals.  Cattle,  goats, 
deer,  rabbits,  hares,  buffaloes,  dogs,  cats,  lions,  tigers,  etc.,  are 
all  liable  to  it,  while  it  occurs  more  rarely  in  birds,  chickens,  ducks 
and  geese.  In  the  Zoological  gardens  at  Copenhagen  infected 
horseflesh  was  fed  to  wild  animals  with  the  results  that  two  leop- 
ards, two  pumas,  three  coons,  four  bears,  three  polecats  and  one 
beech  marten  contracted  the  disease.  A  similar  observation  was 
made  in  Posen,  where  two  silver  lions,  one  jaguar,  one  hyena, 
three  coons  and  one  large  tiger  were  made  acutely  ill,  but  survived. 
Amongst  domestic  animals  the  disease  may  be  contracted  through 
infected  straw. 

77 


78  GENERAL  PATHOLOGY 

A  number  of  investigators,  notably  Da  vain  and  Rayer  in  1850 
and  PoIIender  in  1 855,  had  observed  bacilli  in  the  blood  and  organs 
of  animals  ill  of  splenic  fever,  but  the  proof  of  the  relation  of  this 
organism  to  the  disease,  its  isolation  and  manner  of  infection  was 
furnished  by  Koch  in  his  earliest  work,  in  which  he  laid  the  founda- 
tion for  modern  bacteriological  technique.  The  discovery  of  in- 
fection by  persistent  anthrax  spores  in  instances  in  which  the  bacilli 
themselves  were  not  responsible  established  the  pathogenic  impor- 
tance of  spores  even  though  the  bacilli  had  been  killed  by  heat  or 
antiseptics. 

In  appearance  the  anthrax  bacillus  is  a  large  rod  of  4-5,  even 
lo/u  and  of  i-ij£  in.  thickness.  It  is  non-motile  and  large  enough 
to  be  easily  recognized,  even  unstained  in  the  blood  or  organ 
juice  (spleen).  The  rods  lie  between  red  blood  cells  as  clear,  cylin- 
drical elements  in  pairs,  short  chains  or  isolated.  They  stain 
easily  with  the  usual  anilin  dyes  and  are  positive  to  Gram.  Fixa- 
tion is  preferably  done  by  pouring  alcohol  on  a  slide  and  rapidly 
burning  this  off.  The  bacilli  appear  then  well  in  detail. 

In  arrangement  they  often  show  an  end  to  end,  joint-like  attach- 
ment, and  as  their  extremities  are  not  flat,  but  depressed  in  form 
of  a  concave  curve,  several  joints  give  the  impression  of  a  bamboo 
cane.  Noticeable  is  a  capsule  in  recent  state,  but  not  in  culture. 
Anthrax  bacillus  is  an  aerobe  and  grows  well  only  in  air,  although 
existence  under  anaerobic  conditions  is  possible.  The  temperature 
limits  are  pretty  wide,  from  I5°C.  to  43°C.,  but  growth  at  low 
temperature  is  much  slower. 

Growth  takes  place  on  the  ordinary  culture  media,  best  in 
alkaline  reaction,  but  acid  reaction  is  tolerated.  It  also  develops 
well  on  barley,  corn,  maize,  wheat  and  hay  infusions  which  are 
excellent  culture  media.  It  liquefies  gelatine  and  grows  in  the  form 
of  long,  wavy  filaments  which  project  in  every  direction  and  form 
thickly  coated  masses.  Milk  is  coagulated,  and  eventually  digested, 
litmus  reduced  and  some  acid  is  formed. 

Spores  develop  in  the  presence  of  nascent  oxygen  only  they  are, 
therefore,  not  found  in  the  animal  organism.  This  can  be  readily 
observed  in  the  hanging  drop  where  the  spores  only  make  their 
appearance  in  about  24  hours.  In  culture  they  are  found  only 


ANTHRAX  79 

where  the  growth  has  overstepped  the  height  of  its  development, 
that  is,  in  change  from  favorable  to  unfavorable  environment. 
They  are,  like  other  spores,  highly  refractive  oval  bodies,  are 
surrounded  by  a  dense  membrane  and  can  be  stained  by  special 
methods,  which  is  hardly  necessary  to  recognize  them.  New  bacilli 
develop  from  the  spores,  under  favorable  conditions,  in  several 
hours,  through  a  polar  opening  and  divest  themselves  of  their 
spore  membrane  in  snake-like  fasion.  While  the  anthrax  bacilli 
themselves  are  no  more  resistant  than  many  other  micro-organisms 
the  spores  are  extremely  resistant  (10  to  12  years),  and  this  resist- 
ance seems  to  vary  in  different  strains. 

A  5  per  cent,  carbolic  acid  solution  kills  the  spores  in  from  two  to 
forty  days,  steam  in  from  three  to  twelve  minutes,  boiling  water 
in  over  five  minutes.  The  bacilli  themselves  succumb  at  55°C. 
Sunlight  and  air  kill  the  spores  in  2%  hours.  Air  excluded, 
they  remain  viable  50  hours.  1:1000  bichloride  of  mercury  kills 
spores  in  about  half  an  hour.  It  is  important  that  certain  other 
bacteria,  especially  staphylococci,  streptococci,  bacillus  pyocyaneus 
and  the  pneumococcus  are  antagonistic  to  bacillus  anthracis.  The 
blood  serum  of  certain  animals,  especially  of  white  rats,  is  said  to 
be  destructive  to  it.  Pigs  and  dogs  on  the  other  hand  are  very  sus- 
ceptible, cold-blooded  animals  less  so.  Poor  nutrition,  cold  and 
hunger  favor  infection. 

Methods  of  Injection.  Infection  may  occur  through  three  ports 
of  entrance.  First,  by  direct  contact  or  vaccination  through  abra- 
sions or  scarification  before  a  protecting  granulation  tissue  is 
formed  (frequent  in  butchers).  Second,  by  feeding,  when  infection 
takes  place  through  the  intestinal  tract.  Koch  showed  that  in  this 
method  the  bacilli  are  probably  all  destroyed,  but  the  spores  mature 
in  the  intestinal  tract  and  penetrate  into  the  mucous  membrane. 
Thus  characteristic  ulcerations  are  formed.  The  third  method  is 
through  inhalation.  This  was  first  demonstrated  by  Biichner  and 
occurs  through  direct  inhalation  of  anthrax  spores.  This  in- 
fection involves  the  lungs  and  probably  requires  a  large  quantity 
of  spores. 

Infected  animals  continue  in  apparent  health  some  hours  after 
inoculation,  then  suddenly,  in  from  one  to  two  days  in  rabbits  and 


8o  GENERAL  PATHOLOGY 

guinea  pigs,  show  signs  of  acute  illness.  They  fall  down,  have  con- 
vulsive movements  and  die  rapidly,  usually  without  fever.  Autopsy 
discloses  an  edematous,  gelatinous  exudate  at  the  point  of  inocula- 
tion and  anthrax  bacteriemia,  that  is,  all  organs  are  swarming  with 
bacilli.  The  blood  is  thick  and  tarry;  its  CO2  is  increased;  O 
diminished.  The  spleen  is  much  enlarged,  soft,  pulpous  (splenic 
fever).  Hemorrhages  and  necroses  occur  in  other  organs. 

In  man  the  lesions  are  similar  although  the  splenic  swelling  is 
less.  In  the  intestinal  anthrax  occur  edematous  infiltrations 
hemorrhages  and  carbuncles  of  the  mucous  membrane.  In  respira- 
tory anthrax  (wool-sorter's  disease)  is  found  hemorrhagic  infiltra- 
tion of  the  nasal  mucous  membrane,  larynx  and  trachea.  Infarcts 
of  the  lung,  serous  pleuritis.  Rigor  mortis  may  be  absent.  Putre- 
faction is  rapid.  In  man  hemorrhagic  meningitis  develops  some- 
times very  rapidly  and  early  leads  to  death. 

The  cutaneous  infection  is  characterized  by  the  so-called  malig- 
nant carbuncle  or  pustule.  This  may  be  either  primary  and  con- 
stitute the  principal  picture  of  the  disease  or  skin  lesions  may  follow 
or  accompany  an  internal  infection. 

Prophylaxis.  Destruction  of  the  cadaver  by  rapid,  deep  burial 
(6  feet  under  ground  where  spores  cannot  form)  is  the  only  safe 
prevention.  The  disease  is  spread  only  by  free,  not  buried,  bacilli, 
and  the  ground  is  easily  contaminated  by  secretions  of  infected 
animals  from  mouth  and  nose.  In  man  the  disease  is  contracted 
almost  entirely  by  those  in  contact  with  animals  susceptible  to  the 
disease  or  their  hides  or  hair.  Such  are  butchers,  horse-hair 
weavers,  wool  packers,  shepherds,  meat  inspectors,  longshoremen 
carrying  hides,  glove  and  brush  makers,  etc.  Isolated  cases  due  to 
infected  shaving  brushes  have  been  reported. 

Protective  vaccination  against  anthrax  infection  in  animals  is  now 
practiced  with  attenuated  bacilli.  Good  results  have  been  reported 
from  this  method,  and  also  from  a  serum. 

Symptomatic  Anthrax.  A  disease  known  as  symptomatic  anthrax 
occurs  chiefly  amongst  sheep,  cattle  and  goats.  It  also  goes  under 
the  name  of  quarterevil  or  black  leg.  It  does  not  occur  in  man,  but  in 
animals  it  may  be  confused  with  anthrax  on  account  of  a  superficial 
similarity.  It  is  due  to  a  spore-forming  bacillus,  residing  in  the  soil, 


BACILLUS  SUBTILIS  81 

(bacillus  cbauvei),  with  rounded  ends,  motile  and  possessing  oval 
spores  which  are  larger  than  the  rod,  giving  somewhat  the  impres- 
sion of  a  "  whetstone. "  Sometimes  they  are  distinctly  spindle 
shaped,  and  the  immature  spores  are  seen  in  the  center  of  the  bacil- 
lary  body  (clostridium).  The  organism  is  an  anaerobe,  grows 
easily  and  is  Gram  negative.  It  produces  a  soft,  puffy  swelling  in 
the  legs,  which  spreads  and  is  accompanied  by  fever.  The  bacilli 
remain  mostly  local  and  are  scarce  in  other  parts  of  the  body. 
Infection  occurs  through  skin  abrasions  and  wounds  of  extremities. 

BACILLUS  SUBTILIS.  There  exist  a  number  of  bacilli  which  resem- 
ble the  anthrax  bacillus  morphologically  and  may  give  rise  to  some 
confusion.  Most  important  of  this  groups  is  the  bacillus  subtilis 
or  hay  bacillus.  It  differs  from  anthrax  by  being  motile  and  by 
equatorial  instead  of  polar  development  from  the  spores.  Culturally 
it  rapidly  liquefies  gelatine  and  forms  a  pellicle  on  the  surface  of 
broth. 

The  members  of  the  bacillus  subtilis  group  are  generally  inhabit- 
ants of  the  soil,  widely  distributed,  and  generally  non-pathogenic, 
being  bacteria  of  decomposition.  There  exist,  however,  some  patho- 
genic varieties  which  lately  have  been  recognized  in  impor- 
tance in  relation  to  inflammations  of  the  eye  and  various,  often 
severe,  ophthalmias  (contamination  of  water  in  operating  rooms 
and  wards). 


CHAPTER  XVI 

THE  PLAGUE  BACILLUS 

BUBONIC  plague  or  black  death,  has  always  been  a  much-feared 
disease,  especially  in  Oriental  countries,  on  account  of  its  devastat- 
ing epidemic  character.  Repeatedly  it  has  swept  over  the  whole 
world  and  decimated  it.  To-day  it  is  almost  entirely  confined  to  the 
Orient,  particularly  China,  whence  it  is  occasionally  brought  to  the 
Western  continent.  The  bacillus  was  discovered  in  cadavers  of 
victims  and  in  the  pus  of  glands  by  Kitasato  and  Yersin,  inde- 
pendently, in  1893.  An  accidental  infection  with  a  laboratory  cul- 
ture occurred  in  Vienna  in  1898. 

The  bacillus  is  short,  thick,  with  rounded  ends  (1.51*  by  0.511), 
mostly  single,  rarely  united  or  in  chains.  Older  cultures  show  many 
involution  forms  and  pleomorphism.  It  is  non-motile  and  does  not 
form  spores.  It  stains  well  with  aniline  dyes  and  in  pus  shows  polar 
staining  after  fixation  in  alcohol  (no  heat)  and  is  negative  to  Gram. 
In  the  tissues  some  of  the  bacilli  are  capsulated,  a  feature  which  is 
not  very  common. 

Cultures  are  easily  obtained  on  meat  media  between  20°  to 
38°C.  in  neutral  or  slightly  alkaline  reactions.  Agar  and  gelatine 
are  better  suited  than  broth.  It  grows  compact  with  granular, 
indented  margin.  Milk  is  slightly  acidified  without  coagulation. 
The  bacilli  are  easily  killed  by  several  hours  of  drying.  Dry  heat 
destroys  them  in  one  hour;  steam  in  a  few  minutes,  but  cold  is 
withstood  for  years  (10  years  in  an  ice  chest).  To  direct  sunlight 
and  antiseptics  they  succumb  readily. 

Patbogenicity.  The  bacilli  enter  the  animal  body  through 
the  skin  or  the  respiratory  tract.  Thus  originate  lymphatic  (bu- 
bonic) or  pneumonic  plague.  The  bacilli  are  then  generally  dis- 
seminated through  the  body  (bacteriemia),  and  cause  wherever 
they  anchor  severe  hemorrhagic,  necrotic  and  gangrenous  inflam- 
mations. The  sputum  contains  an  abundance  of  bacilli  and  is, 

82 


THE  PLAGUE  BACILLUS  83 

therefore,   a  dangerous  source  of  infection.   All  patients  suffer 
from,  and  die  with,  severe  cardiac  depression. 

Most  susceptible  are  rats  and  guinea  pigs,  and  in  rats  the  disease 
occurs  spontaneously  and  is  epidemic,  hence  they  are  an  important 
factor  in  infection  of  docks  and  ships.  Rats  show  the  same  autopsy 
findings  as  man:  marked  hemorrhagic  bubo  formation  (necrotic, 
purulent  inflammation  of  glands)  and  other  evidences  of  a  severe 
septicemia.  Squirrels  have  also  been  found  infected  in  epidemics. 
The  disease  may  easily  spread  through  contaminated  clothing, 
linen  and  other  objects  with  which  dying  vomiting  and  coughing 
rats  come  in  contact.  The  rats  themselves  are  reinfected  from  other 
rats'  excretions  and  human  dejecta.  Infection  from  man  to  man  is 
also  common.  One  attack  confers  immunity.  Artificial  immuniza- 
tion by  vaccines  (attenuated  bacilli)  has  been  reported  successful 
in  some  instances. 


CHAPTER  XVIII 

THE  TETANUS  BACILLUS,  BACILLUS  OF  MALIGNANT 
EDEMA,  BACILLUS  AEROGENES 

TETANUS  :  Lockjaw.  While  this  disease  is  ordinarily  of  less  fre- 
quency than  other  wound  infections,  it  acquires  great  importance 
in  times  of  war,  where  it  is  apt  to  carry  off  a  large  number  of 
victims.  Certain  localities,  moreover,  are  more  exposed  to  tetanus 
infection  than  others,  especially  where  the  soil  has  long  been  culti- 
vated and  fertilized,  when  the  ground  abounds  in  anerobic  bac- 
teria. That  tetanus  is  eminently  a  wound  infection  has  been  recog- 
nized for  generations,  and  its  peculiar  nervous  manifestation,  were 
formerly  attributed  to  peripheral  nerve  irritations.  Thus  Dupuy- 
tren  described  a  case  in  which  a  piece  of  a  whip  cord  was  found 
in  the  scar  of  a  wound  around  the  ulnar  nerve.  But  it  remained 
unsettled  why  such  foreign  bodies  should  cause  lockjaw  in  one 
case  and  not  in  another.  The  endemic  frequency  in  certain  loca- 
tions was  also  peculiar. 

When  later  the  infectious  character  of  hydrophobia  and  of  the 
wound  fevers  were  generally  recognized  it  was  possible  to  assume  a 
similar  etiology  for  tetanus.  Gradually  this  view  was  strengthened, 
especially  after  the  direct  transmission  of  the  disease  by  material 
from  tetanic  patients  to  animals  had  been  demonstrated.  The 
cultivation  of  the  bacillus  of  tetanus  was  finally  accomplished  by 
Kitasato  in  Koch's  laboratory  by  anaerobic  methods. 

Morphology.  Very  recent  gelatine  cultures  show  the  bacillus 
2  to  4^  long,  0.3  to  o.5ju  broad,  free  or  in  threads.  In  10  to  14  days  a 
very  characteristic  spore  formation  takes  place.  The  spore  is  a 
round,  polar  body  of  I  to  1.5/4  diameter,  which,  like  a  head,  sits  on 
the  end  of  the  bacillus  giving  it  the  appearance  of  a  drumstick. 
The  bacilli  are  actively  motile,  are  easily  stained  and  are  Gram 
positive.  Kitasato  cultivated  it  on  agar  plates  in  an  atmosphere  of 
hydrogen  after  he  had,  by  previous  culture  and  heating  to  8o°G, 


THE  TETANUS  BACILLUS  85 

succeeded  in  fractional  sterilization  of  the  culture  from  other 
contaminating  bacteria.  The  success  of  the  cultivation  depended, 
therefore,  upon  the  resistant  spores.  On  gelatine  the  culture  con- 
sists of  thicker  central  masses  with  radiating  or  straight  streaky 
extensions.  The  culture  medium  is  softened  by  the  formation  of 
small  gas  bubbles.  Peptonization  and  gas  formation  are  character- 
istic. The  gas  is  methane  and  CO2.  The  blood  serum  is  not  a  good 
culture  medium.  The  organism  is  strictly  anaerobic.  O  is  bacteri- 
cidal to  it. 

Pathogenicity.  The  bacilli  occur  superficially  in  cultivated  fertil- 
ized soil  in  the  form  of  spores  and,  if  protected  from  the  air,  persist  a 
long  time.  They  are  probably  also  introduced  into  the  animal  gut 
through  products  of  the  soil.  The  bacillus  is  not,  strictly  speaking, 
parasitic.  It  easily  succumbs  to  the  bactericidal  properties ,  of 
blood  and  remains  at  the  point  of  inoculation  (mostly  introduced  in 
wounds,  through  the  umbilicus  in  infants  or  by  vaccination).  More- 
over infection  takes  place  only  when  bacilli  are  introduced  in  large 
numbers  and  especially  where  extensive  trauma  and  death  of  tissues 
(compound  fracture)  have  occurred.  These  furnish  a  good  culture 
medium  and  lessen  antibactericidal  action  of  blood  and  tissues. 

Tetanus  neonatorum  occurs  by  infection  through  the  umbilicus. 
The  period  of  incubation  is  days  to  weeks  (latent  spores).  There 
may  be  local  factors  interfering  with  bacteriolysis  favoring  in- 
fection (see  under  Bacillus  Aerogenes  and  Immunity).  Clinically 
the  disease  is  characterized  by  an  increasing  and  progressing 
muscular  rigidity.  The  muscles  of  the  jaw  and  neck  are  primarily 
affected,  then  those  of  the  chest  and  abdomen.  Hands  and  fore- 
arms remain  free.  The  rigidity  is  increased  by  temporary  exacerba- 
tions or  crises.  Consciousness  remains  clear.  Profuse  perspiration  is 
frequent. 

The  prognosis  is  bad,  the  mortality  being  about  88  per  cent.  The 
chronic  form  gives  a  somewhat  better  prognosis.  Death  occurs 
from  asphyxia  and  heart  paralysis.  Autopsy  does  not  disclose 
characteristic  lesions.  The  local  confinement  of  the  bacilli,  their 
rapid  disappearance  at  port  of  entrance  and  the  symptoms  show 
that  the  disease  is  eminently  a  toxic  one  and  not  dependent  upon 
a  bacteriemia  or  septicemia. 


86  GENERAL  PATHOLOGY 

The  toxine  of  the  organism  is  obtained  from  anaerobic  broth 
cultures.  It  is  very  highly  poisonous,  but  in  a  different  degree  to 
different  animals.  For  example,  the  horse  is  twelve  times  more 
susceptible  than  the  mouse,  but  this  is  30,000  times  as  susceptible 
as  the  hen,  0.000,005  c.c.  is  sufficient  to  kill  a  mouse. 

The  tetanus  toxine  has  a  strong  affinity  for  the  cells  of  the  nervous 
system.  Wassermann  and  Takaki,  in  a  fundamental  study,  found 
that  the  poison  is  made  innocuous  when  mixed  first  with  the  brain 
substance  of  a  pig  and  subsequently  injected.  In  other  words  the 
toxine  has  been  bound  by  the  nerve  cells  of  the  pig's  brain.  It  is  not 
unlikely  that  other  cells  of  the  body  possess,  at  least  to  some  vary- 
ing degree,  the  ability  to  fix  tetanus  toxine.  The  different  suscepti- 
bility of  animals  may  depend  upon  this  phenomenon. 

An  important  feature  is  that  the  toxine  is  not  transported  by  the 
blood  or  lymph  stream,  but  seems  to  be  adsorbed  by  the  end  organs 
of  the  motor  nerves  and  then  is  diffused  through  the  axis  cylinders 
to  the  ganglion  cells  of  the  central  nervous  system. 

Antitoxine.  Antitoxine  formation  is  similar  to  that  of  diphtheria 
and  has  acquired  considerable  importance  in  the  prevention  of 
tetanus.  Its  curative  value  is,  however,  almost  nil,  except  in  the 
chronic  form,  partly  because  the  toxines  travel  by  the  axis  cylinder 
of  nerves,  being  thus  protected  from  antitoxine  contact,  partly  on 
account  of  a  very  firm  union  of  toxine  to  nervous  cells  and  finally 
because  the  regeneration  of  the  nervous  system,  after  being  once 
injured,  is  very  poor  or  impossible.  Antitoxine  is  prepared,  as  in 
diphtheria,  by  injection  of  very  small  doses  of  attenuated  toxine 
with  iodine  bichloride  into  horses.  This  is  followed  by  gradual 
appearance  of  antitoxine  in  the  blood.  In  the  recent  war  its  prophy- 
lactic value  has  been  conclusively  demonstrated. 

BACILLUS    OF    MALIGNANT    EDEMA. 

This  micro-organism  was  first  seen  by  Pasteur,  and  then  more 
thoroughly  studied  by  Koch,  who,  in  1881,  proposed  the  name  on 
account  of  its  characteristic,  local  inflammatory  action.  It  is  very 
widely  distributed  in  the  soil  and,  therefore,  exists  also  in  the  intes- 
tines of  animals  and  man. 

Morphology.     Long,   slender  rod,  somewhat  like  the  anthrax 


BACILLUS  AEROGENES  87 

bacillus,  but  longer  and  thinner  (normally  3  to 8ju  long).  Frequently 
it  occurs  in  long  threads  or  more  or  less  homogeneous  filaments. 
The  bacillus  is  motile.  Spores  form  at  2o°C.  and  are  oval.  They 
are  either  polar  or  equatorial.  Generally  the  organism  is  reported 
as  Gram  negative,  by  some  as  positive. 

Cultivation.  Like  most  bacteria  of  the  soil  the  bacillus  of  malig- 
nant edema  is  a  strict  anaerobe.  It  grows  well  on  most  culture 
media,  especially  in  the  presence  of  glucose.  Characteristic  is  a 
radiating  manner  of  extension  which  on  gelatine  and  glucose  is 
attended  with  gas  (bubble)  formation.  Milk  is  slowly  coagulated, 
and  growth  is  good  on  potato.  It  is,  on  the  whole,  not  very  sensi- 
tive to  the  reaction  of  the  culture  media. 

Patbogenicity.  The  bacillus  is  pathogenic  for  mice,  guinea  pigs, 
rabbits,  horses,  sheep,  pigs,  cattle,  some  birds  and  man.  Inoculation 
produces  at  the  site  of  entrance  in  about  a  day  a  marked  edema- 
tous  (watery)  hemorrhagic  inflammation,  extending  into  the  deeper 
tissues  and  to  the  neighboring  lymph  glands.  Gas  is  formed  and 
the  tissues  become  thereby  elastic  and  crepitant  (emphysema). 
The  disease  is  primarily  local,  only  shortly  after  death  bacilli 
invade  generally  and  diffusely  through  the  body.  The  disease  is  rare 
in  man,  but  occurs  occasionally  after  extensive,  dirty  trauma  (com- 
pound fractures)  and  accompanies  extensive  suppuration.  It  has 
been  observed  after  abortion  in  women.  Protection  is  conferred 
by  the  disease  or  artificially  filtered  sera  of  infected  animals. 

THE   BACILLUS   AEROGENES 

Bacillus  Aerogenes  Capsulatus  (Welcbii).  Is  the  cause  of  gase- 
ous edema  or  gangrene,  and  acquired  great  importance  in  the  late 
war.  The  organism  was  discovered  by  Welch  (1892)  in  the  body 
of  a  man  dying  from  aortic  aneurysm,  who  at  autopsy  showed  a 
peculiar  gaseous  emphysema  of  the  skin,  internal  organs  and  blood. 
It  is  probably  identical  with  Frankel's  bacillus  phlegmones  em- 
phymatosae  (1893).  Subsequently  the  organism  has  been  found  to 
be  a  common  inhabitant  of  the  soil  and  intestines. 

Morphology.  This  bacillus  is  a  large  organism,  from  3  to  5/x 
long,  occurs  in  pairs,  groups,  but  not  in  chains,  occasionally  also 


88  GENERAL  PATHOLOGY 

in  coccoid  forms.  It  is  non-motile  and  produces  spores.  It  stains 
well  with  the  ordinary  dyes  and  with  Gram,  sometimes  more  or 
less  irregularly.  Characteristic  is  its  broad  capsule  when  in  tissues.1 
Capsule  is  not  seen  in  artificial  cultivation,  except  in  blood 
serum. 

The  bacillus  is  an  anaerobe,  but,  under  certain  conditions  may 
exist  as  an  aerobe.  It  grows  on  neutral  or  alkaline  gelatine,  better 
with  the  addition  of  glucose.  Here  a  very  characteristic  strong, 
stormy,  gas  production  occurs.  Colonies  are  grayish  white  or 
brownish;  at  end  of  24  hours  about  0.5  to  i.o  mm.  in  size  and  later 
as  large  as  2  to  3  mm.  In  broth  it  grows  only  anaerobically,  also 
in  milk  which  is  coagulated.  The  resistance  of  the  bacillus  is  not 
great.  It  dies  at  a  temperature  of  58°C.  Spores,  of  course,  persist. 

Patbogenicity  is  ordinarily  very  limited  and  mostly  only  a  ter- 
minal or  even  post-mortem  invasion.  The  organism  cannot  grow  in 
living,  circulating  blood.  But  in  wounds  into  which  earth  has  been 
forced,  as  in  compound  fractures  or  by  prolonged  contact  of  crushed 
wounds  with  the  soil  (soldiers  or  aviators  on  field  of  battle)  the 
organism  is  apt  to  show  an  alarming  malignant  virulence.  In  the 
last  war  it  was,  therefore,  a  much  feared  battle-field  infection, 
producing  local  swelling,  reddening,  and  abundant  gas  formation 
with  hemorrhagic  necrosis  of  skin  and  muscles.  Extension  occurs 
often  very  rapidly  and  sometimes  involves  the  whole  body,  in- 
creasing after  death.  The  body  may  then  show  a  disfiguring  skin 
bloating  and  emphysema.  But  even  under  reduced,  weakened 
conditions  and  in  shock,  infection  occurs  only  in  a  relatively  small 
number  of  cases  and,  as  in  tetanus,  a  special  concatenation  of  cir- 
cumstances seems  required  for  its  pathogenic  action.  Bullock  and 
Cramer  have  recently  shown  that  the  presence  of  calcium  salts 
artificially  injected  at  the  site  of  inoculation  or  elsewhere  (but 
then  not  so  readily)  prevents  normal  lysis  of  these  bacteria  and 
makes  the  animal  susceptible  to  infection. 

Contamination  with  an  earth  containing  calcium  salts  may, 
therefore,  render  an  animal  susceptible  by  breaking  down  the  normal 

lTo  demonstrate,  spread,  dry  and  fix.  Pour  on  a  drop  of  glacial  acetic  acid 
for  a  fe.w  moments,  drain  and  cover  at  once  with  strong  solution  of  gentian  violet. 
Best  examined  fresh  in  drop  of  a  solution  of  sodium  chloride. 


BACILLUS  AEROGENES  89 

resisting  powers.  Magnesium,  on  the  other  hand,  exerts  a  protec- 
tive action.  A  similar  combination  of  circumstances  is  apparently 
required  for  the  production  of  tetanus.  The  mechanism  of  action  is 
not  yet  clear,  but  seems  to  depend  upon  a  local  change  brought  about 
by  the  calcium  salts  at  the  site  of  injection  (see  under  Immunity). 
Autopsy  in  gas  gangrene  shows  frothy  blood  and  organs  with 
extensive  hemorrhagic  necrotic  breakdown,  especially  at  the  point 
of  entrance.  Besides  its  local  importance,  this  bacillus  seems  to  be 
concerned  in  certain  troublesome  intestinal  putrefactions  with 
much  butyric  acid  formation  and  may  cause,  according  to  Herter, 
general  anemia. 


CHAPTER  XVIII 
TYPHUS  EXANTHEMATICUS 

TYPHUS  EXANTHEMATICUS  is  a  highly  contagious,  fatal,  epidemic 
disease  with  a  short  incubation  period  (8  to  15  days),  characterized 
by  high  fever,  a  scarlatiniform  and  purpuric  rash,  skin  sloughs 
and  large  spleen.  The  disease  has  long  been  recognized  as  one 
making  its  appearance  and  ravages  in  dirt  and  filth  with  hunger 
and  famine.  In  the  Middle  Ages  it  was  an  important  pestilence. 
The  last  war  brought  it  again  to  the  attention  of  the  world  by  wide 
occurrence  in  the  East  and  Near  East.  The  disease  is  brought  to 
the  Western  World  by  immigrants  and  possibly  exists  in  the 
United  States  in  a  milder,  aborted  form  under  the  name  of  Brill's 
disease,  although  this  is  not  settled. 

Etiology.  The  infecting  agent  exists  in  the  circulating  blood  of 
infected  persons  and  may  be  transmitted  to  monkeys.  It  is  stated 
that  inoculation  with  blood  filtered  through  a  Berkefeld  filter 
renders  monkeys  refractory  to  further  infection.  Until  recently 
attempts  to  isolate  a  specific  micro-organism  have  failed.  In  1915 
Plotz  found  by  anaerobic  cultivation  a  bacillus  which  he  and  some 
others  believed  to  be  the  cause  of  the  disease. 

By  incubating  2  c.c.  of  freshly  drawn  blood  in  serum  glucose 
ag&r  (5  c-c-  serum,  20  c.c.  2  per  cent,  glucose  agar),  deep  colonies 
develop  in  16  days  of  a  small  pleomorphous,  Gram-positive 
bacillus,  straight  or  slightly  curved.  It  does  not  form  spores,  but 
shows  occasional  polar  bodies.  It  produces  acid  on  dextrose,  malt- 
ose, galactose  and  inuline,  but  no  gas.  It  is  an  obligatory  anaerobe. 
Confirmation  of  its  etiological  relation  seemed  to  be  supported  by 
the  specific  agglutination  test  and  pathogenic  effect  on  guinea  pigs 
which  develop  high  fever  and  a  large  spleen.  But  whether  this  is  a 
true  typhus  infection  is  uncertain  and  agglutination  tests  in  typhus 
appear  unreliable.  Against  it  is  the  negative  evidence  of  Zinsser, 
Sellards,  Hopkins  and  others  who  failed  to  isolate  Plotz's  organ- 
ism and  especially  the  observations  of  Ricketts,  Wilder  (1910), 

90 


TYPHUS  EXANTHEMATICUS  91 

Helger  and  Prowazeck,  (1913)  Rocha  Lima  (1915),  Toepfer 
Schiissler,  Noeller,  Weigle,  and  Walbach  and  Todd,  who  have 
discovered  a  plesiomorphous  coccoid  and  bacillary  organism  in 
the  alimentary  epithelial  cells  of  the  body  louse  and  in  the  vascular 
endothelium  of  typhus  patients.  It  is  apparently  identical  with 
forms  seen  by  Ricketts  in  Mexican  typhus.  Rocha  Lima  introduced 
the  term  "Rickettsia  Prowazecki"  for  it  to  honor  the  two 
pioneer  investigators  of  typhus  who  themselves  succumbed  to  the 
disease.  The  "  Rickettsias  "  seem  to  constitute  a  group  of  so  far 
poorly  understood  forms  of  which  one  other  has  been  found  in 
trench  fever.  Others,  however,  have  been  seen  without  diseases, 
but  never  intercellular,  in  body  lice.  Their  relations,  nature  and 
position  are  quite  uncertain.  They  have  not  been  definitely  identi- 
fied, much  less  cultured.  Strong  is,  therefore,  still  of  the  belief  that 
the  etiology  of  typhus  is  undetermined.  E.  W.  Schultz  regards  the 
"Rickettsias"  as  protozoa.  Whatever  organism  may  be  the  cause, 
it  is  certain  that  the  infection  occurs  principally  through  the  body 
louse,  although  infection  through  saliva  (cough)  is  by  some  con- 
sidered possible.  NicoIIe  and  others  succeeded  in  transmitting  the 
disease  by  the  feces  or  crushed  remains  of  infected  lice  and  their 
bite  is  either  infected  or  becomes  infective  through  fecal  contam- 
ination. The  most  important  louse  is  here  the  body  louse,  not 
the  head  louse. 

Monkeys  and  guinea  pigs  are,  as  stated,  susceptible  and  the 
latter  develop  characteristic  brain  lesions  (Endothelial  cell 
swelling  and  proliferation,  thrombosis  and  perivascular  cell 
infiltrations). 

Prophylaxis.  The  only  efficient  prophylactic  measure  is  ex- 
tinction of  vermin.  No  other  disease  has  demanded  so  many  victims 
among  doctors  and  nurses.  Silk  underwear  has  been  recommended 
as  repugnant  to  lice.  Isolation  of  garments  for  about  a  week  kills 
the  lice  by  starvation.  The  same  can  be  accomplished  more  quickly 
by  heat  and  kerosene.  The  great  Serbian  epidemic  of  1915  was 
controlled  by  cleanliness. 

An  antityphus  serum  has  been  prepared  by  NicoIIe  from  the 
blood  of  asses  by  injection  of  an  emulsion  of  leucocytes  and  spleen 
of  infected  guinea  pigs.  It  is  said  to  be  effective. 


CHAPTER  XIX 
INFLUENZA 

THE  name  influenza  has  been  given  to  an  infectious  epidemic 
disease,  which,  occurring  in  waves  lasting  several  years  and  spread- 
ing over  the  whole  world  from  east  to  west  is  characterized  by  mild 
or  very  severe,  often  rapidly  fatal,  catarrhal  and  serous  hemor- 
rhagic  inflammations  of  the  respiratory  tract,  severe  constitutional 
disturbances  and  long-continued  marked  prostration.  It  is  not 
certain  whether  all  the  epidemics  which  have  been  regarded  as 
influenza  are  of  uniform  etiology,  or  even  one  and  the  same  disease. 
In  a  severe  epidemic  from  1890  to  1892,  Pfeiffer  discovered  a 
bacillus,  now  bearing  his  name,  which  since  then  has  been  regarded 
as  the  cause  of  the  disease. 

PJeiffer's  Bacillus.  This  is  a  very  small  organism,  rarely  larger 
than  1.5/1  long  and  0.3/1  thick.  It  does  not  form  spores,  is  non-motile 
and  possesses  no  capsule.  It  has  little  affinity  for  aniline  stains  in 
aqueous  solution.  It  is  best  stained  by  carbol  fuchsin  diluted  1:10, 
4  to  5  minutes  without  decolorization.  It  is  Gram  negative.  Culture 
is  best  done  on  dilute  blood  agar.  The  presence  of  hemoglobin  is 
indispensable  and  necessary.  Recently  culture  media  containing 
an  oleate  have  been  employed.  Colonies  appear  as  minute,  trans- 
lucent, round,  discrete  points  in  about  18  hours.  They  are  not 
viable  long  and  have  very  little  power  of  resistance  to  drying  and 
antiseptics.  According  to  Grassberger  the  Bacillus  influenzas  grows 
more  luxuriantly  on  ordinary  blood  agar  (5  to  10  per  cent,  blood) 
in  the  vicinity  of  colonies  of  pyogenic  cocci  and  especially  of  staphy- 
lococcus  aureus.  Bruere  recommends  a  medium  consisting  of  nu- 
trient agar,  made  with  a  dead  twenty-four  hours'  staphylococcus 
aureus  broth  to  which  i  per  cent,  defibrinated  blood  has  been 
added  while  the  agar  is  still  hot  (9O°C). 

Patbogenicity.  The  exact  pathogenesis  of  this  bacillus  has 
always  been  somewhat  uncertain.  Pfeiffer  cultivated  the  micro- 
organism from  the  bronchial  secretions  of  influenza  patients.  In 

92 


INFLUENZA  93 

subsequent  investigations  Wassermann,  Clemens,  Koppen,  Pick 
and  others  had  great  difficulty  in  demonstrating  its  presence  even 
in  the  acute  stage,  and  Kretz  and  others  showed  its  occurrence  in 
non-pathogenic  strains  and  as  partner  in  mixed  infections.  Even 
among  virulent  types  strains  seem  to  vary  greatly.  The  bacillus 
does  not  generally  penetrate  deeply  into  the  tissues  and  blood 
cultures  have  been  generally  negative,  but  influenza  infections  of 
joints  have  been  reported  by  Franke. 

Specific  agglutination  with  high  serum  dilutions  of  infected 
persons  has  not  been  successful  in  general  experience.  Fichtner 
says:  "My  hope  to  find  a  clinically  useful  diagnostic  method  by 
the  agglutination  test  has  been  much  lowered.  Genuine  agglutina- 
tion may  occur,  butapositive  result  must  be  interpreted  with  great 
care."  Recent  investigators  claim  better  results  in  some  instances. 

Animals  are  refractory  to  the  infection,  but  its  toxine  (extracted 
with  chloroform)  is  fatal  to  rabbits.  Intratracheal  injection  and 
rubbing  a  pure  culture  of  the  bacillus  upon  the  unbroken  nasal 
mucosa  produces  influenza  symptoms  in  monkeys.  Here  also  the 
reaction  is  probably  largely  toxic.  Immunity  is  slight  and  short. 
The  bacterial  toxine  is  a  strong  nervous  depressor. 

The  most  recent  influenza  epidemics  (1918,  1919)  have  been 
extremely  severe,  but  have  so  far  not  allowed  an  absolutely  clear 
definition  of  the  etiological  question.  As  cultural  methods  and 
experience  have  improved,  the  influenza  bacillus  has  been  found 
in  increasing  numbers,  rarely,  however,  alone;  generally  with  the 
pneumococcus,  but  also  streptococci  and  staphylococci.  It  is  held  by 
some  that  the  strain  of  the  last  epidemic  is  a  particularly  virulent 
one.  It  is  possible  that  we  are  dealing  with  symbiotic  infections 
of  several  pathogenic  bacteria,  but  so  far  very  little  is  known 
about  symbiotic  infections.1 

Kocb-Weeks  Bacillus.  Closely  related  to  the  bacillus  of  Pfeif- 
fer  is  the  Koch- Weeks  bacillus  which  occurs  in  a  form  of  contagious 
conjunctivitis. 

Most  influenza  epidemics  have  been  associated  with,  or  fol- 
lowed by,  peculiar  cases  of  encephalitis,  i.e.,  inflammations  of 

1  Olitsky  has  isolated  lately  a  filtrable  virus  and  this  has  been  confirmed  by 
Loewe. 


94  GENERAL  PATHOLOGY 

the  brain  (perivascular  cell  infiltration,  thrombosis,  hemorrhages 
and  softenings).  Sometimes  meningitis  is  present.  The  pontine 
location  is  preferred  and  purpuric  hemorrhages  may  be  visible  in 
the  brain  substance.  In  earlier  epidemics  gross  softenings  had  been 
observed.  In  the  last  sweep  of  influenza  softenings  (infarcts)  were 
microscopic.  Leichtenstern,  Nauwerck  and  others  look  upon  it  as 
an  influenza  infection.  The  latter  cultivated  (1895)  bacilli  similar 
to  Pfeiffer's,  from  the  ventricular  fluid  in  one  case.  Others,  Flexner, 
for  example,  deny  any  direct  relation  and  believe  that  influenza 
simply  prepares  a  suitable  soil  for  another  infection. 

Emulsions  of  the  diseased  brain  injected  into  rabbits  produce  the 
disease  in  them.  Loewe  and  Strauss  claim  isolation  of  an  organism. 
It  is,  according  to  them,  a  filtrable  virus. 


CHAPTER  XX 
THE  SPIRILLA 

SPIRILLA  and  SPIROCHETES  are,  as  compared  to  bacteria,  higher 
types  of  micro-organisms.  They  are  tapering,  filamentous  threads, 
very  motile  and  flagellated.  Some  discussion  has  arisen  as  to  their 
exact  biological  position.  They  stand  close  to  the  lowest  animal 
forms,  protozoa,  more  especially  the  spirochetes.  Occasionally 
they  are  identified  with  them.  But  the  modern  view  distinguishes 
spirilla  from  protozoa  by  lack  of  nucleus,  blepharoplast  and  of  an 
undulating  membrane  and  by  a  different  method  of  division. 
Moreover,  some  spirilla  appear  during  certain  phases  of  their 
development  as  bacilli.  The  following  are  the  most  important: 

CHOLERA.  By  cholera  we  understand  an  epidemic  disease  which 
was  confined  to  Asia  before  the  nineteenth  century.  Since  then  it 
has  visited  Europe  and  America.  In  1817  a  severe  epidemic  com- 
menced in  India,  involved  the  whole  peninsula  and  spread  over 
the  whole  world.  Since  that  time  there  have  occurred  five  great 
epidemics:  1817  to  1823;  1826  to  1837;  184610  1862;  186410  1875; 
the  last  commenced  in  India,  in  1883  went,  by  way  of  Egypt, 
Asia  Minor  and  Russia  to  Germany,  which  it  reached  in  the  sum- 
mer of  1892.  It  increased  in  intensity  to  1894,  reached  Hamburg 
and  from  there  England,  and,  in  isolated  cases  the  United  States 
of  America.  The  origin  of  all  of  these  epidemics  was  the  mouth 
of  the  Ganges  River,  where  the  disease  is  endemic.  At  the  beginning 
of  the  last  epidemic,  in  1883,  Koch  was  commissioned  by  the  Ger- 
man Government  to  proceed  to  Egypt  and  to  investigate  this 
disease.  Koch  recognized  it  as  an  intestinal  infection  and  saw  this 
organism,  later  named  the  comma  bacillus,  in  the  intestinal  contents 
and  wall  of  victims.  He  succeeded  in  its  cultivation,  established 
its  etiological  relation  and  traced  the  source  to  polluted  water 
tanks.  Thus  it  was  possible  successfully  to  prevent  spread  of  the 
infection  and  later  to  establish  immunity  by  protective  vaccination. 

95 


96  GENERAL  PATHOLOGY 

Cholera  is  primarily,  as  Koch  found  it,  an  intestinal  infection 
and  the  chief  evidences  are  in  the  gut.  If  the  duration  of  the  disease 
is  only  very  short  (hours)  the  intestinal  contents  are  of  "rice 
water"  consistency,  with  mucous  flakes  of  reddish  tint.  The  mucosa 
appears  injected.  In  later  stages  the  lining  epithelium  of  the  gut 
desquamates,  the  intestinal  wall  appears  turbid  and  in  spots 
pinkish,  especially  in  areas  rich  in  lymphoid  tissue.  The  intestinal 
contents  show  an  almost  pure  culture  of  "comma"  bacilli  and 
these  may  penetrate  into  the  mucosa  after  necrosis  of  the  lining 
epithelium.  Then  other  organisms,  such  as  bacillus  coli,  follow  in  its 
path.  Very  severe,  late  lesions  resemble  somewhat  those  of  typhoid 
(so-called  cholera  typhoid).  The  mucous  membrane  appears  dark, 
almost  black,  necrotic,  hemorrhagic,  especially  in  the  region  of 
the  ileo-cecal  valve.  The  intestinal  contents  are  then  foul  and 
bloody. 

Morphology.  The  organism  is  a  very  motile,  flagellated,  non- 
spore-forming  spirillum.  It  stains  by  the  ordinary  methods,  but 
not  by  Gram.  The  motility  is  so  great  that  Koch  compared  it  to  a 
swarm  of  midgets.  The  germ  appears  as  a  short  rod  with  a  distinct 
curve,  comma-shaped,  occasionally  in  an  S  curve.  Koch  regarded 
it  originally  as  a  pure  bacillus,  but  it  is  now  known  that  the  bacil- 
lary  form  is  only  a  phase  of  the  spirillum  or  vibrio.  The  spirillum 
develops  from  the  so-called  bacilli.  Both  are,  therefore,  frequently 
found  together.  Under  difficult  conditions  of  existence,  however, 
only  spirals  are  found.  Each  spirillum  possesses  a  single  flagellum 
attached  to  one  end. 

Cultivation  is  easy.  It  grows  luxuriantly  on  the  usual  media.  On 
gelatine  appear  small  white  spots  growing  from  below  towards  the 
surface.  Gelatine  is  liquefied,  so  that  in  older  cultures  the  plate 
appears  studded  with  small  holes  caused  by  evaporation  of  the 
liquid  gelatine.  Later  the  colonies  become  granular  and  yellowish. 
This  is  its  characteristic  manner  of  growth.  A  pellicle  is  formed  on 
the  surface  of  bouillon.  On  milk  this  spirillum  is  only  short  lived, 
as  it  is  destroyed  by  acidity.  Characteristic  is  indol  formation  in 
bouillon  and  the  reduction  of  nitrates  to  nitrites,  so  that  only  the 
addition  of  a  few  drops  of  H2SO4  is  required  for  the  production 
of  the  rose-red  color,  the  so-called  "nitroso  indol  reaction."  To 


THE  SPIRILLA  97 

develop  indol  it  is  best  to  use  a  i  per  cent,  solution  of  Witte's 
peptone  +  0.5  per  cent.  NaCI.  The  medium  must  be  alkaline. 

Resistance.  The  organism  is  very  susceptible  to  drying.  Bouillon 
cultures  are  thus  killed  in  two  hours.  Infection  through  dust  and 
air,  therefore,  is  not  possible.  Moreover  inhalation  into  the  lung 
does  not  seem  to  be  pathogenic.  Boiling  is  immediately  destructive, 
a  temperature  of  3O°C.  kills  in  five  minutes.  Antiseptics  are  poorly 
tolerated;  i  to  23,000,000  bichloride  solution  kills  in  from  five  to 
ten  minutes.  Even  distilled  water  destroys  in  24  hours.  The  growth 
of  the  spirillum  is  retarded  by  putrefactive  bacteria.  Sewage  kills 
it  in  24  hours.  Dry  food  also  does  not  preserve  it  and  fluids  must  be 
of  alkaline  reaction  to  preserve  it  at  all. 

Patbogenicity.  Spontaneous  cholera  is  a  disease  of  man  and  not 
of  animals.  Animals,  however,  may  be  made  more  or  less  suscepti- 
ble if  the  gastric  juice,  which  is  antagonistic,  is  neutralized.  Its 
infectious  character  in  man  has  been  established,  not  only  bacterio- 
logically,  but  experimentally,  by  accidental  means.  In  1884  a 
worker  in  Koch's  laboratory  was  infected  with  one  of  the  cultures 
from  India.  Severe  infections  occurred  in  Pfeiffer  himself  and  in 
Pfuhl  in  the  Berlin  Institute  for  infectious  diseases.  In  1895  an 
assistant  in  the  bacteriological  laboratories  of  Hamburg  infected 
himself  with  a  drop  of  a  culture  intended  for  a  guinea  pig,  and  died. 
Pettenkofer  and  Emmerich  experimented  on  themselves  after 
first  neutralizing  their  gastric  juice  and  then  drinking  water  con- 
taining some  cholera  bacilli.  In  Pettenkofer  resulted  a  severe 
diarrhea  and  Emmerich  almost  died  of  a  typical  cholera  attack. 
The  disease  runs  in  man  a  characteristic  course,  with  abdominal 
cramps,  rice-water  stools,  great  prostration,  anuria,  subnormal 
temperature,  collapse  and  death. 

Infection  seems  to  occur  largely  by  polluted  water,  and 
outbreaks  of  the  disease  are,  on  account  of  the  short  period  of 
incubation,  explosive.  When  in  1892  the  city  of  Hamburg 
became  infected  through  its  drinking  water  by  pollution  through 
the  river  Elbe,  the  contiguous  city  of  Altona,  which  filtered 
its  water,  escaped  entirely.  Important  is  the  carrier,  who  himself 
may  be  spared,  but  who  spreads  the  infection  from  place  to 
place.  During  an  epidemic  the  number  of  carriers  is  increased. 

7 


98  GENERAL  PATHOLOGY 

One  attack  of  cholera  usually  leaves  an  individual  immune  from 
future  attacks. 

The  organism  does  not  produce  a  readily  dissociable  toxine,  like 
diphtheria  or  tetanus,  but  only  an  endotoxine,  bound  to  the  body 
of  the  spirillum  and  liberated  by  its  destruction.  It  seems  to 
remain  largely  local,  in  the  gut,  the  cholera  vibrios  not  penetrating 
into  the  body.  The  nature  of  the  poison  is  not  at  present  under- 
stood. Agglutination  with  the  patient's  serum  is  irregular  and 
uncertain  and  here  not  of  diagnostic  value. 

Immunization  has  been  attempted  and  lately  practiced  with 
what  appears  to  be  good  results.  Immunized  animals  develop  a 
bacteriolytic  (dissolving)  property  in  their  serum,  which  seems  to 
be  specific.  The  serum  has  preventive,  but  no  curative  value,  unless 
injected  almost  immediately  after  infection.  KoIIe  advised  prophy- 
lactic vaccination  with  cultures  killed  by  heating  to  5O°C.  This 
has  been  successfully  used  in  an  epidemic  in  Japan. 

Closely  related  spirilla  or  vibrios  occur  in  large  number.  They 
differ  biologically  in  virulence  and  are  not  bacteriolysed  by  cholera- 
immune  serum. 

VINCENT'S  ANGINA.  This  is  an  ulcerating  membranous  angina 
pharyngis  and  stomatitis,  sometimes  closely  simulating  diph- 
theritic inflammations.  It  is  apparently  caused  by  a  constantly 
present,  long,  slender,  spindle-shaped  or  fusiform  organism,  which 
is  non-motile  and  Gram  negative.  Spreads  show  at  the  same  time  a 
variable  number  of  spirilla  with  the  bacilli.  Their  relationship 
has  been  a  matter  of  question.  It  is  now  held  that,  as  in  cholera, 
bacilli  and  spirilla  represent  phases  in  the  development  of  one 
organism  (Tunnecliffe).  Similar  spirilla  and  bacterial  forms  have 
been  found  in  other  ulcerating  and  necrotic  stomatitis. 

RELAPSING  FEVER.  This  has  been  of  great  interest  because 
Obermeier  demonstrated  in  1868,  long  before  the  days  of  bacteri- 
ology, a  living  organism  as  the  cause  of  the  disease.  He  published 
his  investigations  in  1873  and  in  the  same  year  died  of  cholera. 
He  described  the  organism,  which  now  bears  his  name,  as  a  fine, 
motile  thread.  Its  infectious  nature  was  fully  corroborated  by 
subsequent  observers,  especially  through  the  direct  inoculation 
of  infected  blood  into  man  and  monkeys. 


THE  SPIRILLA  99 

Relapsing  or  recurrent  fever  is  characterized  by  attacks  of 
fever  separated  by  completely  afebrile  intervals.  The  attack 
commences  with  a  chill,  the  temperature  rises  to  39°,  40°,  4i°C. 
and  drops  in  a  few  days  by  crisis,  usually  below  the  normal.  After 
a  few  days  of  complete  rest  follows  another  attack,  and  this  is 
repeated  three  to  four  times.  The  fever  chart  becomes,  therefore, 
quite  characteristic  so  that  the  diagnosis  is  easy. 

The  spirillum  is  always  present  in  the  blood  in  the  fever  attacks, 
appears  with  the  rise  in  temperature  and  disappears  with  the  crisis. 
It  is  absent  during  the  intervals.  Occasionally  jaundice  is  present. 
Mortality  is  not  high,  2  to  5-10  per  cent.  The  spleen  is  large  and, 
post-mortem,  shows  marked  lymphoid  swelling. 

Morphology.  The  spirillum  of  Obermeier  is  a  fine,  spiral,  taper- 
ing thread  of  no  more  than  ifj,  in  thickness  and  loto  20-4  io/*  in 
length.  It  possesses  between  6  to  20  curves  or  convolutions.  The 
organism  does  not  show  a  particular  structure  or  differentiation. 
In  fresh  blood  the  motility  is  so  rapid  and  active  that  individual 
movements  are  seen  with  difficulty.  They  are  boring  (motion 
around  longitudinal  axis),  to  side  or  lateral,  and  forward  and  back- 
ward. The  boring  movement  seems  most  frequent.  Flagella  have  not 
been  definitely  demonstrated.  Individuals  are  generally  free,  inde- 
pendent, solitary,  not  in  groups.  Spores  have  not  been  discovered. 

Schaudinn  maintained  that  the  organism  does  not  belong  to  the 
bacteria,  but  is  a  protozoon,  and  in  possession  of  a  nucleus,  bleph- 
aroplast  and  undulating  membrane.  Novy  and  Knapp  deny 
this  and  claim,  in  addition,  that  multiplication  occurs  by  trans- 
verse, not  longitudinal,  division.  However,  morphology,  biology 
and  pathogenic  characters  put  it  very  close  to  the  protozoa. 

The  spirillum  of  Obermeier  stains  with  the  ordinary  aniline  dyes, 
but  not  by  Gram's  method.  Preferable  are  basic  methylene  blues, 
as  Romanowsky's,  Giemsa's,  Wright's  or  Leishman's  stains  or 
impregnation  with  a  silver  salt.  It  does  not  grow  on  ordinary  media, 
but  Noguchi  succeeded  in  culture  by  adding  infected  blood  to 
sterile  ascitic  fluid  containing  pieces  of  fresh  rabbit's  kidney. 

Method  oj  Injection.  It  had  been  recognized  for  many  years 
that  recurrent  fever  is  essentially  a  disease  of  unclean,  dirty 
surroundings.  In  Russia,  inhabitants  of  prisons,  barracks,  tene- 


ioo  GENERAL  PATHOLOGY 

ments  and  tramps  were  well  known  to  contract  it.  In  Africa 
Europeans  were  infected  frequently  along  caravan  roads. 

Dutton  and  Todd  showed  then  that  the  African  form  of  relaps- 
ing fever  is  transmitted  through  the  horse  tick.  This  resides  in  dry 
ground  and  under  the  roof  of  inns  and  road  houses.  The  female  is 
especially  dangerous.  It  attacks  at  night,  sucks  itself  full  of  blood 
and  retires  again.  Spirilla  thus  taken  in  pass  the  stomach,  develop 
in  the  alimentary  tract  at  rather  high  temperatures  from  30°  to 
35°C.  and  reach  the  ovaries.  They  infect  the  eggs  and  these,  when 
hatched,  remain  infective  to  the  next  generation.  The  excreta  of 
the  tick  also  contain  the  spirillum  and  the  tick  remains  infective 
for  1 8  months.  Infection  occurs  probably  by  the  bite  contaminated 
with  the  excretions  of  the  tick. 

Of  greater  importance  in  the  European  method  of  transmission 
is  the  body  louse.  The  lice  infect  their  eggs  and  infection  in  man  is 
brought  about  by  crushing  the  louse,  the  bite  apparently  being 
ineffective.  Eggs  may  carry  the  infection  12  to  30  days  after  inges- 
tion  of  the  parasite  by  the  louse. 

It  is  generally  held  that  immunization  occurs  during  the  fever 
attack  through  a  powerful  lytic  substance  which  appears  in  the 
blood  and  dissolves  the  organism.  After  crisis  the  organism  can  only 
be  found  in  the  bone  marrow  and,  possibly,  other  protected  parts 
of  the  body.  But  there  is  some  evidence  supporting  the  view  that 
during  the  afebrile  intermissions  the  spirillum  passes  through  a 
developmental  cycle  and  alters  its  form. 

WEIL'S  DISEASE.  In  1914  Inada  and  Ido  demonstrated  a  spiril- 
lum or  spirochete  in  the  liver  of  patients  with  infectious  jaundice 
(Weil's  disease) :  Spirochaeta  ictero-hemorrhagica.  It  is  transmitted 
through  the  urine  and  the  rat. 

Similar  organisms  have  been  demonstrated  by  Noguchi  in 
yellow  fever. 

SYPHILIS.  The  interesting  history  of  this  most  important 
infection  has  already  been  referred  to  in  connection  with  gonor- 
rhea. It  is,  according  to  old  testimony  and  the  recent  historical 
researches  of  Sudhoff  of  great  antiquity  and  general  occurrence. 
But  it  was  first  brought  prominently  before  the  world  in  the  great 
epidemic  at  the  end  of  the  fifteenth  century. 


THE  SPIRILLA  101 

The  name  syphilis  was  introduced  by  Fradaktpr  (^485  t6, 1553), 
in  a  poem  in  which  Syphilus,  a  mythical  king's  sony  was  afllicted 
with  the  disease  for  blasphemy  of  Apol.ta.  ,Alf  attempts  tt> 
find  the  etiological  factor  failed,  until  Schaudinn  with  Hoffman 
(1905)  in  following  up  the  claims  of  Siegel  of  the  discovery  of 
another  organism  in  the  secretions  of  syphilitic  sores,  discovered 
a  delicate  spirochete,  the  relation  of  which  to  syphilis  is  now  well 
established. 

The  disease  is  practically  always  acquired  by  direct  contact, 
sexual  or  otherwise,  with  a  syphilitic  sore  or  secretions.  Extrageni- 
tal  infection  has  been  much  exaggerated,  but  certainly  occurs  as 
by  kissing,  tattooing,  etc.  The  organism  is  relatively  easily  dis- 
covered in  the  recent  state  in  India  ink  preparations,  in  which  the 
spirochetes  stand  out  as  clear,  delicate,  fine  spirals  against  the 
dark  background  (mix  fluid  India  ink  with  a  drop  from  a  syphilitic 
sore,  let  dry  and  examine  with  oil  immersion).  Even  better  is  the 
fresh  preparation  with  the  dark  field  illumination  in  which  their 
motility  may  be  clearly  observed.  They  may  be  demonstrated  in 
fixed,  very  thin  films  by  Giemsa's  stain  (stain  for  1 6  to  24  hours, 
after  fixation  with  absolute  ethyl  or  methyl  alcohol). 

Spirocheta  pallida  or  Treponema  pallidum  is  an  exceedingly  fine, 
weakly  refracting  screw-shaped  body,  characterized  by  steep  narrow 
curves.  Its  length  is  from  4  to  10  to  14^  and  it  is,  therefore,  decidedly 
smaller  than  other  spirochetes.  The  individual  possesses  6  to  14 
curves,  but  there  are  forms  with  20  to  24  curves.  Towards  the  ends 
the  body  shows  attenuation.  Movement  in  the  fresh  specimens  is 
pronounced,  principally,  as  in  other  spirochetes,  rotation  around  its 
longtitudinal  axis,  also  forward  and  backward  and  sideways. 
Actual  locomotion  hardly  occurs,  so  that  an  organism  remains  in 
the  field  of  vision  for  a  long  time.  Both  extremities  possess  flagella. 
The  finer  structure  is  not  quite  settled.  Schaudinn  regarded  it  as 
a  protozoon. 

It  is  important  to  remember  that  other  spirillar  parasites  occur 
frequently  in  and  around  the  genitals  and  in  the  mouth.  From 
these  spirocheta  pallida  is  easily  distinguished  by  much  finer 
forms,  lesser  refraction  and  numerous  delicate  curves  (especially 
from  the  common  Spirocheta  refringens). 


102  GENERAL  PATHOLOGY 

Cuifivia'on.w/is  jfipli  Accomplished  pure  by  Noguchi,  after  Schere- 
sche^^yJaad,  obtained  impure  cultures.  The  method  is  essentially 
th&tf  £nipfo:y«d  ihitbfe. cultivation  of  the  spirilla  of  relapsing  fever. 
It  has  been  possible  to  reproduce  the  disease  in  monkeys  by  inocula- 
tion with  pure  culture,  also  in  rabbits,  especially  in  the  testicle. 

Occurrence.  The  spirocheta  pallida  is  a  pure  parasite,  and  so  far 
has  only  been  found  in  syphilitic  lesions,  especially  abundant  in  the 
chancre,  mucous  patches  and  skin  lesions.  But  late  syphilitic 
gummatous  affections  have  also  disclosed  its  presence,  sometimes, 
however,  only  after  very  prolonged  search  and  in  very  scarce 
number.  In  sections  they  are,  even  in  active,  early  lesions,  more 
difficult  to  find.  In  late  lesions  they  often  disappear,  being  either 
destroyed  or  assuming  another  phase  form.  This  is  still  uncertain. 
In  syphilitic  embryos,  or  fetus,  or  premature  infants,  they  are 
very  abundant  in  the  liver.  The  organisms  lie  in  endothelial  cells 
of  vessels  and  in  the  syphilitic  inflammatory  infiltrations  around 
blood  vessels  and  lymph  spaces.  They  probably  travel  in  the  peri- 
vascular  lymph  sheaths. 

So-called  parasyphilitic,  or  late  nervous,  manifestations  of 
syphilis  (paresis  and  tabes  dorsalis)  aie  now  known  to  be  truly 
syphilitic  by  demonstration  of  the  spirocheta  pallida  in  the  inflamed 
meninges  (Noguchi).  Although  the  syphilitic  lesions  are  generally 
local  in  expression  the  spirochetes  are  found  generalized  in  most 
organs  (Warthin).  Well  adapted  for  the  demonstration  of  the 
Spirocheta  pallida  is  the  silver  method  of  Levaditi  (impregnation 
of  small  blocks  after  formalin  fixation  with  a  silver  salt — nitrate 
of  silver — and  pyridine  solution,  then  reduction  with  pyrogallic 
acid;  tissues  appear  bright  yellow;  spirochetes  are  dark  brown  or 
black). 

Immunity  in  syphilis  and  the  serological  diagnosis  by  comple- 
ment fixation  (Wassermann  reaction,  see  Immunity,  page  117). 


CHAPTER  XXI 
PATHOGENIC  PROTOZOA 

TRYPANOSOMES.  Trypanosomes  (from  rpinravov  =  to  bore)  are 
free,  swimming  protozoa  which  occur  as  parasites  in  the  blood 
and  other  fluids  of  man  and  animals.  They  have  of  late  acquired 
great  importance  in  relation  to  certain  tropical  disease,  especially 
sleeping  sickness.  They  are  transferred  from  one  animal  to  another 
through  the  bite  of  leeches,  insects  or  vermin.  A  large  number, 
about  sixty,  have  been  described. 

The  most  important  of  these  protozoa  is  Trypanosoma.  Gambi- 
ense  (Dutton,  1902).  This  is  spindle-shaped,  about  17  to  28/i  long 
and  1.4  to  2ju  broad.  From  the  anterior  end,  that  is,  the  end  which 
moves  forward  as  the  animal  swims,  projects  a  whip-fashioned 
flagellum,  about  one-half  the  length  of  the  organism.  It  is  terminal 
and  free.  The  proximal  two-thirds  of  the  body  are  connected  by  a 
band  of  body  substance  which  is  continued  like  a  ruffle  along  the 
side  of  the  organism  to  within  a  short  distance  of  the  blunt  posterior 
end  and  terminates  abruptly  where  the  flagellum  ends  in  the 
blepharoplast.  This  is  the  undulating  membrane.  The  blepharo- 
plast  is  a  sort  of  second  nucleus,  the  real  nucleus  being  situated 
in  the  center  of  the  protozoon.  Multiplication  takes  place  by  longi- 
tudinal division. 

Transmission  and  Patbogenicity.  For  a  long  time  a  peculiar 
sickness  has  been  prevalent  in  the  tropics,  known  as  sleeping  sick- 
ness. It  is  characterized  by  headache,  lassitude,  later  profound 
lethargy,  muscular  weakness  and  tremor.  As  the  disease  progresses 
the  patient  wastes,  utter  exhaustion  follows,  bedsores  and  finally 
exitus.  The  disease  runs  a  course  of  about  three  years  and  in  its 
last  stages  resembles  the  ending  of  the  general  paralysis  of  the 
insane.  Physically  here  is  only  noted  enlargement  of  lymphatics 
(Sir  Patrick  Manson).  The  trypanosome  was  first  seen  by  Dutton 
in  the  blood  of  a  sea  captain  of  a  steamer  from  the  Gambia,  who 
was  supposed  to  be  suffering  from  malaria.  This  patient  died  in 

103 


104  GENERAL  PATHOLOGY 

England  in  1903.  In  the  same  year  Dutton  and  Todd  examined 
other  individuals  in  the  Gambia  and  found  trypanosomes  among 
1000  persons  in  .six  natives  and  one  quadroon. 

The  true  relation  of  the  trypanosomes  to  sleeping  sickness  was 
first  established  by  Castellani,  who  found  them  in  the  cerebro- 
spinal  fluid  of  patients.  This  was  later  confirmed  by  Bruce,  Nabarro, 
Laveran  and  others.  The  disease  was  already  well  known  to  the 
explorer  Livingstone  in  1857,  who  recognized  that  the  so-called 
"tsetse  fly"  seemed  to  have  some  relation  to  it.  It  was  then  sup- 
posed to  be  due  to  a  poison  of  the  fly.  The  exact  connection 
between  the  fly  and  the  disease  was  worked  out  by  Bruce  in  1895  to 
1 897.  Flies  were  fed  on  infected  animals  kept  in  captivity  for  days 
and  placed  on  healthy  dogs.  These  flies  were  not  infective,  but, 
if  flies  were  fed  on  infected  animals  and  immediately  transferred, 
or  within  24  to  48  hours,  infection  occurred.  This  disproved  the 
infectious  nature  of  the  fly  and  demonstrated  that  it  only  acted  as 
a  carrier.  With  the  discovery  of  the  trypanosome  the  role  of  the 
fly  became  even  clearer,  for  the  fly  is  simply  the  transmitter  of  the 
trypanosome.  The  fly,  the  so-called  "tsetse  Ry,"Glossina  palpalis, 
is  a  large  brown  insect  with  a  loud,  humming  sound.  It  lives  in  the 
soft  mud  on  the  banks  of  the  stream  and  feeds  on  crocodiles. 
Kleine  is  of  the  opinion  that  the  method  of  transmission  is  not  a 
direct  one,  but  that  the  micro-organism  undergoes  a  develop- 
mental cycle  in  the  body  of  the  fly.  Thus,  he  found  that  the  insect 
does  not  become  infective  until  about  18  hours  have  elapsed  from 
the  time  of  feeding.  This  is  still  an  unsettled  point. 

Numerous  other  trypanosomes  or  related  organisms  have  been 
discovered.  Some  relatively  harmless,  others  the  cause  of  severe 
tropical  diseases.  Among  the  latter  the  trypanosome  of  Leishman- 
Donovan  is  of  importance  in  the  production  of  so-called  kalar- 
azar,  dum  dum  or  black  fever. 

MALARIA.  Since  antiquity  malaria  has  been  an  extremely  com- 
mon disease  in  the  tropics  and  hot  northern  countries.  It  is  preva- 
lent in  Italy,  Central  America  and  the  Southern  States  of  the 
United  States.  The  disease  is  characterized  by  a  high  intermittent, 
remittent  or  continuous  fever  with  severe  constitutional  disturb- 
ances, headaches,  even  delirium  and  coma. 


PATHOGENIC  PROTOZOA  105 

The  fever  is  generally  preceded  by  definite  chills.  In  the  interval 
patients  enjoy  relative  health.  In  1880  Laveran,  of  France,  in 
Algiers,  announced  the  discovery  of  a  parasite,  the  plasmodium 
malariae,  in  the  blood  of  patients  suffering  from  the  disease. 
Nothing  much  was  known  of  the  organism  and  the  manner  of 
infection  until  in  1890  Golgi,  of  Italy,  described  the  cycle  of  develop- 
ment in  the  human  blood.  In  1895  Sir  Ronald  Ross  discovered 
its  cycle  in,  and  mode  of  transmission  through,  the  mosquito 
(anopheles)  and  in  1898  W.  G.  MacCallum  showed  the  sexual  fer- 
tilization of  the  parasite. 

Infection  through  an  insect,  and  particularly  the  mosquito,  had 
already  been  suspected  by  Sir  Patrick  Manson,  and  he  also  sus- 
pected that  swamps  might  act  as  medium  of  transmission.  The 
organism  occurs  in  several  types,  each  with  a  cycle  of  development 
of  its  own  and  thus  leading  to  different  fever  attacks  which  are 
essentially  expressions  of  discharge  of  spores  into  the  circulating 
blood.  Thus,  we  can  distinguish: 

PARASITE  DISEASE          |  HOST  |  TRANSMITTING  INSECT 


Plasmodium  Malariae.  .  . 
Plasmodium  Vivax  
Plasmodium  Falciparum 

Quartan  fever 
Tertian  fever 
Aestivo-autumnal 
fever 

Man 
Man 
Man 

[  Anopheles  (mosquito) 

Besides  these  most  important  pathogenic  types  for  man,  others 
occur  which  use  monkeys  and  birds  as  intermediate  hosts  and 
other  mosquitoes  (culex)  as  final  habitat.  All  are  sporozoa  and 
live  in  the  red  blood  cells  of  the  infected  animals.  They  possess  a 
double  life  cycle:  (i)  The  asexual  in  the  warm-blooded  intermediate 
host;  (2)  a  sexual,  permanent  cycle  in  the  cold-blooded  host,  a 
mosquito.  The  mosquitoes  are  infected  in  sucking  blood  of  the 
warm  blooded  host  and  these,  in  turn,  are  reinfected  with  bite 
of  the  mosquito. 

i.  Asexual,  Human,  Cycle.  Sporozotes  which  are  harbored 
in  the  salivary  glands  of  the  mosquito  (i.5ju  long  and  o.2/x  broad) 
enter  the  bitten  individual.  They  attach  themselves  to  red  blood 
corpuscles  and  become  spherical  (Schizonts).  Schizonts  appear  as  a 
small  ring  with  an  eccentric  chromatine  spot.  They  grow  steadily, 


106  GENERAL  PATHOLOGY 

feeding  upon  the  hemaglobin  of  the  red  blood  cell,  breaking  the 
hemoglobin  into  clumps.  In  varying  time,  (PL  falciparum  in  24 
or  48  hours;  PL  malariae  in  72  hours;  PL  vivax  in  48  hours),  the 
schizont  matures,  reaches  the  size  of  the  blood  corpuscle  and  the 
parasite  then  divides  into  equal-sized  spores  or  merozoits  (8  in 
PL  malarise;  15  to  25  in  PL  vivax;  8  to  25  in  PL  falciparum).  When 
they  burst  the  cell  and  are  discharged  into  the  circulation,  the 
fever  paroxysm  occurs.  Spores  reenter  new  corpuscles  and  the  cycle 
recommences.  It  is  observed,  however,  that  after  a  time  not  all 
schizonts  change  to  spores,  but  some  develop  into  peculiar  new 
forms  which  were  formerly  regarded  as  degenerative,  but  which 
are  now  known  to  be  sexual  parasites,  so-called  gametes.  The  male 
is  usually  small,  microgamete;  the  female  much  larger,  macro- 
gamete.  They  are  of  different  shape  in  the  various  plasmoidal 
forms.  Of  characteristic,  striking  shape  are  the  crescents  of  PL 
falciparum. 

2.  Actual  mating  of  the  two  sexes  has  so  far  not  been  observed 
in  the  human  blood,  but  occurs  in  the  stomach  of  the  mosquito. 
Here  the  microgamete  becomes  very  active  and  develops  long 
lashing  filaments  (spermatozoa).  These  break  loose,  swim  away 
and  conjugate  with  the  macrogamete,  fertilizing  it.  As  a  result  a 
zygote  or  ookinete  is  formed.  This  attaches  itself  to  the  epithelium 
of  the  wall  of  the  mosquito.  It  penetrates  and  appears  on  the  out- 
side of  the  stomach  wall,  projecting  into  the  body  cavity,  grows 
and  divides  to  form  the  ovocyst,  which  contains  many  sporozoites. 
These  find  their  way  to  the  salivary  gland  of  the  host  and  rest  in 
the  epithelial  cells.  Ultimately  they  are  free  in  the  saliva  and  are 
discharged  through  the  insect's  proboscis  into  the  blood  of  the 
new  host,  possibly  forced  out  by  sneezing  attacks  of  the  mosquito, 
precipitated  through  the  irritating  effects  of  the  human  sweat. 

Demonstration  of  the  plasmodia  in  human  blood  may  be 
made  fresh  or  in  fixed  blood  films  by  Wright's,  Leishman's  or 
Romanowsky's  stains,  during  the  fever  paroxysms.  The  whole 
developmental  cycle  in  the  mosquito  consumes  from  10  to  14  days. 

Plasmodia  are  distinguished  morphologically  from  each  other 
by  their  size,  chromatine  contents,  sporozoit  formation  and  time 
of  development.  The  largest  is  the  plasmodium  of  tertian  fever,  a 


PATHOGENIC  PROTOZOA  107 

relatively  mild  infection.  Most  severe  and  even  fatal  is  the  small 
Plasmodium  falciparum  of  the  irregular  estivo-autumnal  infections. 
The  most  important  serious  effects  of  the  malarial  infection  is 
destruction  of  red  blood  cells  (therefore  large  spleen).  Anemia  and 
cachexia  in  long  continued  cases  follow. 

Prophylaxis.    Quinine  and  extermination  of  mosquito. 

FILTRABLE  VIRUSES.  It  was  found  by  Loffler  and  Frosch  that 
there  exist  micro-organisms  which  are  so  minute  as  to  pass  through 
the  pores  of  porcelain  or  earthen  filters  which  prevent  ordinary 
bacteria  from  passing. 

Some  of  these  micro-organisms  may  be  seen  with  higher  optical 
powers  than  usually  employed,  and  with  the  ultramicroscope,  in 
which  the  object  is  illuminated  intensely  with  diffracted  light, 
not  the  ordinary  transmitted  light,  in  a  dark  field  (this  may  be 
compared  to  sun  rays  passing  directly  into  a  dark  room  through  a 
small  opening  by  which  particles  floating  in  air,  otherwise  invisible, 
may  be  seen).  The  ultramicroscope  shows  thus  objects  of  0.004/11 
which  by  ordinary  transmitted  light  sight  is  limited  to  9. 1  to  o.2/*. 

To-day  about  40  filtrable  viruses  are  known.  In  some,  like  polio- 
myelitis micro-organisms  have  recently  been  isolated,  but  still  need 
confirmation. 

Other  diseases,  like  measles,  scarlet  fever,  smallpox,  etc.,  are 
still  obscure  and  await  solution. 


CHAPTER  XXII 
IMMUNITY 

DEFINITION  AND  CLASSIFICATION.  Immunity  is  generally  de- 
fined as  protection,  defense  or  security  against  an  invasion  (im- 
munis  in  Roman  law  means  to  be  tax-free).  But  this  is  only  partly 
correct,  and  apt  to  convey  an  entirely  erroneous  concept  of  the 
nature  of  immunity.  It  is  true  that  from  the  practical,  medical 
standpoint  those  reactions  impress  us  as  the  most  important  which 
tend  to  preserve  the  individual  against  a  parasite  or  its  actions. 
But  immunity,  in  a  broad  and  scientific  sense,  really  comprises  the 
sum  total  of  all  those  interactive  and  reactive  processes  which 
proceed  in  an  organism  as  a  consequence  of  an  invasion.  Some 
of  these  may  be  protective,  some  are  decidedly  disadvantageous, 
even  fatal. 

Thus  when  an  exudate  is  poured  into  fixed  tissues,  as  the  result 
of  an  inflammatory  irritant,  it  has,  it  is  true,  a  destructive  action 
on  the  inflammatory  irritant,  but,  also  at  the  same  time,  on  tis- 
sues and  their  functions.  This  is  illustrated  in  the  lung,  where  in 
pneumonia  alveolar  spaces  are  blocked,  the  circulation  interrupted 
and  the  lung  and  its  functions  dangerously  incapacitated  by  the 
presence  of  the  exudate.  Again,  in  what  is  known  as  anaphylactic 
shock  (see  later)  the  protective,  defensive  character  is  quite 
overshadowed  by  the  injurious  effects.  In  fact,  immunity  reactions 
have  primarily  no  particular  purpose.  But  in  the  evolution  of  life 
only  those  organisms  have  persisted  which,  by  virtue  of  certain 
characters,  were  able  to  maintain  themselves.  All  others  neces- 
sarily perished.  In  other  words,  animals  were  not  provided  from 
the  beginning  with  purposely  defensive  measures  against  outside 
harmful  influences.  But  only  those  types  survived  which  were 

108 


IMMUNITY  109 

endowed,  amongst  others,  with  processes  now  called  defensive. 
They  were  thus  enabled  to  continue  existence  in  the  face  of  ab- 
normal environments,  and  their  reactions  to  abnormal  environ- 
ment came  to  be  regarded  as  protective  or  defensive. 

It  is,  therefore,  intelligible  that  even  in  those  persistent  animal 
forms  certain  non-protecting  and  even  harmful  processes  and  phases 
of  immunity  continued.  Protective  immunity  is,  therefore,  only 
relative  and  a  phenomenon  of  evolution.  Here,  as  elsewhere,  only 
that  is  preserved  which,  through  a  manifold  endowment,  can 
adapt  itself  to  many  requirements  of  environment.  A  teleological 
conception  of  immunity  as  a  primarily  purposeful,  useful  and  pro- 
tective institution  cannot  be  entertained. 

The  study  of  bacterial  infections  has  shown  that  cause  and  de- 
velopment of  disease  stand  not  in  fixed  relations:  to  the  contrary,  as 
was  fully  discussed  in  the  streptococcus  infections,  they  are  vari- 
able and  depend  upon  relative  determinants  in  the  micro-organism 
and  in  the  host.  We  saw  that  these  determinants  are  partly  of 
quantitative,  partly  of  qualitative  character.  The  disease  depends, 
therefore,  upon  the  conditions  under  which  an  invasion  takes  place. 
Thus,  even  pathogenic  bacteria  may  live  with  a  healthy  host  in 
symbiosis  (carrier). 

The  existence  of  a  parasite  in  a  host  may  be  endangered  by 
general  environmental  factors  which  are  entirely  unsuited  for  its 
own  development.  Cold-blooded  animals,  for  example,  are  re- 
fractory to  infections  of  warm-blooded  animals.  Such  a  state  of 
non-receptiveness  to  an  invader  is  called  natural  immunity.  This 
may  be  absolute,  in  which  the  infective  agent  can  nowhere  anchor 
in  the  body  and  nowhere  grow  on  the  invaded  soil;  or  relative, 
in  which  the  immunity  has  limitations  either  by  the  quantity 
of  infection,1  or  by  conditions  under  which  infection  occurs. 
(Hunger,  for  example,  makes  pigeons  susceptible  to  anthrax 
infection.)  A  great  many  instances  of  natural  immunity  in  higher 
animals  is  relative.  Syphilis  is,  for  example,  less  severe  in  monkeys 
than  in  man  and  exhibits  greater  tendency  to  heal. 

1  A  white  mouse  may  be  killed  by  diphtheria  toxine  sufficient  to  'kill  80 
guinea  pigs;  fowls  cannot  be  killed  by  the  tetanus  bacillus  itself,  but  by  its 
toxine. 


no  GENERAL  PATHOLOGY 

INFECTION.  Any  discussion  of  immunity  must  necessarily  be 
preceded  by  an  understanding  of  infection.  Bacteria  are,  as  has 
already  been  seen,  the  most  important  infecting  agents.  They 
produce  disease  either  locally  or  by  invasion,  frequently  by  both.1 
This  action  is  due  to  toxic  substances  derived  from  their  bodies 
(endotoxines)  or  poisons  which  are  distinct  and  separable  from 
their  bodies  (esotoxines).  These  toxines  must  not  be  confounded 
with  ptomaines,  which  are  alkaloidal  substances  and  products  of 
bacterial  (saprophytic)  life  on  dead  organic  matter.  Moreover, 
bacteria  possess  specific  affinities  for  certain  tissues  and  thus  in- 
fective diseases  show  a  different  attitude  towards  different  age 
periods  depending  upon  the  anatomical  organization  of  these 
periods.  Thus,  for  example,  typhoid  fever,  osteomyelitis  and 
scarlet  fever  are  essentially  diseases  of  youth  (see  under  Disposi- 
tion of  Age). 

Necessary  for  infection  is,  in  every  instance,  (i)the  possibility  of 
bacterial  growth  and  multiplication,  and  (2)  the  establishment  of  a 
definite  interrelation  between  bacteria  and  body  cell.  Where  no 
such  interrelation  occurs  bacteria  continue  harmless:  the  more 
intimate  the  interrelation,  the  greater  the  so-called  "bacterial  viru- 
lence." The  tissue  soil  is,  therefore,  as  important  for  infection  as 
bacteria  themselves. 

The  exact  nature  and  mechanism  of  this  interrelation  is  not  clear 
and  not  thoroughly  understood.  It  is  assumed  by  Vaughan,  Emble- 
ton  and  Thiele  that  this  is  essentially  due  to  cell  enzyme  action 
by  which  bacteria  are  disintegrated  and  poisonous  proteids  set  free 
from  their  bodies.  The  greater  and  more  rapid  the  enzyme  action, 
the  greater  the  bacterial  destruction,  and  the  greater  the  produc- 
tion of  toxic  protein  products.  Virulence  is,  according  to  their 
conception,  really  an  expression  of  the  enzyme  action  of  the  host. 
Non-pathogenic  bacteria  do  not,  or  only  very  slowly,  excite  to 
enzyme  action;  therefore,  to  very  little  reaction  in  the  body. 
Furthermore,  Embleton  and  Thiele  attribute  the  change  from  non- 
virulent  to  pathogenic  organisms  to  a  gradually  developing  sen- 

1A  general  body  permeation  by  bacteria  is  spoken  of  as  septicemia  or  bac- 
teriemia.  If  in  addition  to  this  bacterial  generalization,  there  exist  often  multi- 
ple, local  inflammatory  or  purulent  foci,  it  is  termed  pyemia. 


IMMUNITY  in 

sitiveness  of  the  cells  of  the  host  and  to  a  gradual  production  of 
bacteria  splitting  antibodies. 

According  to  Vaughan,  the  period  of  incubation  in  an  infectious 
disease  corresponds  to  the  time  necessary  for  the  production  of  the 
antibacterial  enzyme.  In  his  opinion  bacterial  disease  depends  upon 
cleavage  of  bacterial  proteins,  similar  to  what  occurs  in  parenteral 
digestion  of  other  proteins.  Vaughan  showed  that  all  proteins, 
would  yield  on  cleavage  with  alkaline  alcohol  a  group  of  toxic  and 
a  group  of  non-toxic  products,  and  he  assumes  that  all  pro- 
teins contain  a  central,  common  and  toxic  chemical  nucleus  to 
which  are  attached  non-toxic  side  chains  which  give  a  protein 
its  specific  character.  Alcohol  as  well  as  cell  enzymes  break  up 
the  protein  molecule  and  set  free  the  central  toxic  nucleus.  Accord- 
ing to  this  conception  the  toxic  effects  of  bacteria  would  be  due, 
not  to  any  specific  poisons  of  their  own,  but  rather  to  toxic, 
non-specific,  protein  cleavage  products,  and  the  question  of 
bacterial  intoxication  would  resolve  itself  into  the  quantity  and 
rapidity  of  bacterial  destruction. 

These  ideas  are  attractive  and  rest  on  a  good  experimental  basis, 
but  they  are  applicable  only  to  certain  types  and  phases  of  infec- 
tion and  they  cannot  be  entertained  as  an  explanation  of  all 
phenomena  of  infection.  In  the  first  place  some  bacteria  like  the 
bacillus  diphtheria,  bacillus  of  tetanus  and  bacillus  botulinus  are 
true  specific  poison  formers,  irrespective  of  any  enzyme  action 
on  their  bodies.  Moreover,  the  affinity  of  certain  bacteria  for, 
and  their  localization  in,  definite  anatomical  districts,  and  the 
consequent  differences  in  anatomical  and  clinical  expressions  of 
infectious  diseases,  are  not  readily  made  clear  by  this  theory. 
We  recognize,  for  example,  a  difference  in  incubation  time  and  in 
character  of  a  typhoid  from  a  streptococcus  or  anthrax  infection. 
While  these  possess  some  common  features,  they  exhibit  charac- 
teristics of  their  own.  Furthermore,  the  peculiar  acquired  symbiosis 
of  some  bacteria,  either  temporary  or  permanent,  with  their  hosts 
is  not  accounted  for  (erysipelas,  gonorrhea,  carriers)  and  the  pheno- 
mena of  individual  disposition  remain  obscure. 

Here  the  recent  observations  of  Besredka  deserve  attention. 
Investigating  the  mechanism  of  typhoid,  paratyphoid  and  dysen- 


ii2  GENERAL  PATHOLOGY 

tery  infections,  he  discovered  that  the  local  susceptibility  or  place 
of  bacterial  anchorage  is  of  great  importance  for  subsequent  in- 
fection and  immunity.  In  animals  which  are  usually  immune  to 
these  infections,  the  previous  administration  of  ox  bile  "sensitized" 
the  intestinal  mucosa  so  as  to  allow  bacterial  attachment  and  inter- 
course with  development  of  a  disease  similar  to  that  in  the  human. 
Such  animals  remained  immune  to  reinfection,  although  the  blood 
showed  no  protective  "substances"  or  "qualities."  In  this  way 
oral  immunity  could  be  established  where  vaccination  failed 
(Dysentery).  Quite  apart  from  the  practical  interest  of  these 
observations,  they  emphasize  a  heretofore  not  sufficiently  appre- 
ciated importance  in  the  relations  between  bacteria  and  specific 
cell  territories,  and  they  may  lead  us  to  a  better  understanding  of 
the  individuality  and  specific  expressions  of  bacterial  diseases 
than  any  theory  which  explains  infection  and  immunity  only  on 
the  basis  of  general  cell  activities. 

Finally,  even  non-pathogenic  bacteria  are,  when  introduced 
into  an  organism,  often  rapidly  disintegrated,  and  still  in  these 
cases  no  characteristic  effects  of  specific  virulence  occur  as  in 
pathogenic  types,  although  a  good  deal  of  foreign  protein  must 
thereby  be  set  free  in  the  animal  organism. 

Thus  it  is  apparent  that  there  must  be  still  other  factors  besides 
those  put  forward  by  Vaughan  which  enter  into  the  pathogenic 
relations  of  bacteria  to  hosts.  Indeed,  considerable  evidence  has 
now  accumulated  which  indicates  that  not  only  chemical,  but 
physical  properties  in  bacteria  and  hosts  are  of  very  great  impor- 
tance and  this  will  be  more  fully  entered  into  in  the  consideration 
of  acquired  immunity. 

ACQUIRED  IMMUNITY.  Our  knowledge  of  acquired  immunity 
was  like  all  scientific  knowledge,  originally  purely  empirical.  The 
first  observations  were  made  in  1791  by  a  country  schoolmaster, 
Plett,  near  Kiel,  on  the  Baltic,  who  noticed  that  persons  who  had 
acquired  cowpox  became  immune  to  smallpox,  and  he  purposely 
introduced  cowpox  virus  into  three  children,  all  of  whom  escaped 
infection.  But  the  first  extensive  and  scientific  experimental  in- 
vestigation into  this  matter  was  carried  on  by  Edward  Jenner,  who, 
on  May  14,  1796,  transferred  some  of  the  contents  of  a  cow  pustule 


IMMUNITY  113 

on  the  arm  of  a  milkmaid  to  the  arm  of  a  boy.  He  subsequently 
introduced  pus  from  a  smallpox  pustule  into  the  arm  of  the  same 
lad  and  found  him  unsusceptible  to  or  protected  against  this  artifi- 
cial smallpox  infection.  This  led  him  to  repeat  his  experiments 
and  to  publish  the  successful  results.  Through  him  the  extermina- 
tion, or,  at  least,  control  of  smallpox  became  possible,  and  the 
disease  was  stripped  of  its  horrors. 

The  type  of  immunity  thus  produced  is  an  example  of  active 
immunity,  that  is,  one  in  which  the  organism,  stimulated  by  an 
attenuated,  non-fatal  dose  of  the  same  or  a  similar  infecting  agent 
(in  this  instance  cowpox)  is  enabled  to  tolerate  a  subsequent 
more  active,  virulent  infection  of  the  same  nature.  This  acquired 
immunity  usually  lasts  for  several  years.  The  act  of  conferring 
immunization  in  this  manner  is  spoken  of  as  vaccination  (from 
vacca  =  cow). 

Eighty  years  elapsed,  curiously  enough,  before  Pasteur  took  up 
again  the  problem  of  active  immunization.  He  experimented  with 
anthrax.  It  occurred  to  him  that  attenuated  (heated)  weakened 
cultures  which  had  lost  the  power  of  spore  formation  and  were 
possessed  of  only  feeble  virulent  powers  might,  nevertheless, 
confer  protection  against  subsequent  stronger  anthrax  cultures. 
He  found  on  using  such  "vaccines"  that  an  actual  immunity  could 
be  established  in  animals.  The  same  principle  guided  him  later 
in  his  famous  immunization  against  hydrophobia  (rabies).  Here 
he  showed,  that,  although  the  infecting  virus  is  unknown,  it  is 
localized  in  the  central  nervous  system  and  can  be  attenuated  by 
drying.  Thus,  by  graded  attenuation  and  successive  vaccination 
with  gradually  stronger  virus,  he  established  successful  immunity, 
even  after  infection  had  occurred. 

Later  investigations  by  others  have  shown  that  not  only 
attenuated,  but  dead  micro-organisms  fulfill  the  purpose  of 
protective  vaccination,  and  these  are  generally  employed  at 
the  present  time  as  prophylactic  measures  against  infectious 
diseases,  especially  typhoid  fever.  Dead  bacteria  are  now  pre- 
ferred, because  the  dosage  can  be  more  accurately  determined. 
The  length  of  such  an  immunity  varies,  being  from  one-half  to 
several  years. 


ii4  GENERAL  PATHOLOGY 

Present  knowledge  of  acquired  immunity  may  be  grouped  under 
three  headings  or,  as  being  represented  by  three  phases: 

1.  Immobilization,  anchoring  of  the  infecting  agent  and  its 
annihilation  (bacteriolysis,  agglutination,  precipitation,  phagocy- 
tosis), that  is,  active  immunity.  The  body  takes  an  active  part  in 
its  production. 

2.  Neutralization  of  poisonous  products  (antitoxic  immunity), 
which  may  be  either  active  or  passive  immunity  because  it  may  be 
transferred  from  one  individual  to  another. 

3.  The  creation  of  conditions  which  are  locally  or  generally 
unfavorable  to  settlement  or  growth  of  infecting  agents  by  modify- 
ing the  physical  and,  possibly  the  chemical  constitution  of  the 
tissues.  This  last,  the  importance  of  which  we  are  only  just  begin- 
ning to  appreciate,  is  really  quite  distinct  from  the  first  two,  for 
it  is  not  a  direct  reaction  against  an  agent  at  all,  but  depends  upon 
cell  and  tissue  properties  and  surroundings  which  do  not  allow 
union  of  infecting  agent  with  cells.  It  is  the  factor  which  is  un- 
doubtedly of  the  greatest  importance  in  natural  immunity.  In 
acquired  immunity  the  first  two  are  only  steps  to  reach  the  third. 
But  it  must  be  admitted  that  in  acquired  immunity  the  creation  of 
conditions  which  are  locally  or  generally  unfavorable  to  settlement 
or  growth  of  bacteria  is  not  always  attained,  or  only  imperfectly. 
Reference  to  this  phase  of  immunity,  the  most  interesting  and  in 
a  way  the  most  important,  will  be  postponed  until  later,  as  the 
problems  of  acquired  immunity  are  best  considered  before  consi- 
dering natural  immunity. 

It  was  in  the  eighties  of  the  last  century  when  Fliigge, 
Nuttall  and  Buchner  made  the  important  discovery  that 
normal  blood  serum  possessed  the  power  to  kill  bacteria,  and 
that  this  "bactericidal"  property  of  the  blood  diminished  with 
the  age  of  the  serum  and  could  also  be  destroyed  by  exposing 
it  to  a  temperature  of  58°C.  This  was  followed  by  the 
discovery  of  Pfeiffer  that  cholera  bacilli  injected  into  the 
peritoneal  cavity  of  cholera-immune  guinea  pigs  were  promptly 
killed  and  dissolved.  This  phenomenon,  known  as  Pfeiffer's 
phenomenon,  was  later  shown  to  take  place  in  vitro  as  well, 
and  this  much  heightened  power  in  cholera  immune  serum  to 


IMMUNITY  115 

dissolve  cholera  bacilli  could  be  diminished  or  destroyed,  as  in 
normal  serum,  by  heat. 

Bordet  discovered,  in  addition,  the  important  fact  that  serum 
which  was  "inactivated"  by  heating,  could  be  "reactivated,"  so  as 
to  regain  its  original  destructive  effect  on  bacteria,  by  adding  any 
other  normal  serum.  The  same  was  found  in  regard  to  other  bac- 
teria, and  from  these  observations  it  was  concluded  that  these 
specific,  strong  bactericidal  properties  of  a  serum  immunized 
against  specific  micro-organisms  are  due  to  two  phases,  or  as  was 
believed,  substances;  the  one  contained  in  every  serum,  which  is 
easily  destroyed  by  heat;  the  other  specific  to  the  immune  serum 
and  stable.  The  first  is  now  commonly  spoken  of  as  complement, 
the  second  as  amboceptor  (ambo  =  both,  capio  =  I  take)  or 
antibody.  Just  how  both  of  these  act  to  produce  solution  of  cells 
is  a  matter  of  discussion  and  does  not  directly  concern  us  here. 
It  is  sufficient  to  remember  that  solution  of  foreign  cells  in  an 
immunized  body  is  brought  about  by  a  combined  action  of  ambo- 
ceptor and  complement,  which,  uniting,  attach  themselves  to  the 
specific  cell  against  which  they  are  directed,  thereby  producing  its 
solution.  Any  substance  which  when  introduced  into  an  animal 
organism  excites  the  formation  of  a  specific  antibody  is  known  as 
antigen.  Bacteriolysis  or  solution  of  bacteria  is,  therefore,  spoken 
of  as  an  antigen-antibody  (amboceptor)  complement  reaction. 

It  must  be  fully  appreciated  at  the  start  that  the  terms  which 
are  employed  in  the  description  of  immunity  reactions  must  not 
be  understood  in  the  sense  of  definite  compounds  which  enter  into 
chemical  reactions.  They  are  hypothetical  conceptions  which  are 
useful  to  visualize  and  fix  in  our  mind  certain  immunity  phases  as 
processes.  None  of  them  has  ever  been  isolated  in  substance,  their 
constitution  remains  entirely  unknown,  but  they  represent  phe- 
nomena in  extremely  complex  colloidal  emulsions  and  suspensions 
and  they  are  probably  not  distinctive  chemical  compounds  for 
the  different  immunity  reactions  in  which  they  take  part  (see 
below). 

Bordet,  continuing  these  researches,  found  that  this  principle  of 
bacteriolysis  does  not  only  apply  to  bacteria,  but  to  other  foreign 
cells,  and  that  the  repeated  introduction  of  foreign  cells,  say  red 


u6  GENERAL  PATHOLOGY 

blood  cells  of  one  animal  into  another,  increases  the  ability  in 
the  serum  of  the  second  animal  to  dissolve  the  hemoglobin  from 
the  cells  injected  from  the  first.  Upon  this  discovery  rests  the  princi- 
ple of  hemolysis. 

If,  for  example,  we  inject  a  rabbit  several  times  with  a  few  c.c. 
(3  to  5)  of  defibrinated  sheep's  blood,  or  better  still,  with  washed 
red  blood  cells  of  sheep,  the  rabbit  serum  acquires  the  property  of 
dissolving  red  blood  cells  of  sheep,  and  we  say  the  rabbit  has  been 
immunized  against  sheep  cells.  In  such  a  case  the  hemoglobin 
passes  into  solution  and  the  test-tube  fluid  assumes  a  claret-red 
hue. 

The  process  of  hemolysis  is  not  a  destruction  of  red  blood  cells, 
but  simply  a  solution  of  hemoglobin  from  the  cell  disks.  These 
remain  behind,  as  a  pale  scaffold,  suspended  in  the  fluid.  Moreover, 
the  hemoglobin  is  not  chemically  altered,  but  simply  assumes 
another  dispersion  phase.  Hemolysis  has  been  shown  to  follow  es- 
sentially the  laws  of  bacteriolysis,  that  is,  in  our  example,  the 
sheep  cells,  when  introduced  into  the  rabbit,  lead  to  the  formation 
of  a  specific  amboceptor  (antibody)  in  the  rabbit  which  in  the 
presence  of  complement  dissolves  the  hemoglobin  from  the  red 
blood  cells  of  sheep.  If  we  inactivate  the  sheep-immune  serum  of 
the  rabbit  by  heating  it,  no  solution  will  take  place,  but  if  we  should 
add  some  normal  serum,  the  solution  will  again  occur,  because 
then  we  supply  the  necessary  complement  to  cells  already  bound 
to  the  antibody.  Such  cells,  which  are  attached  to  their  antibody 
(amboceptor),  but  still  without  complement  are  called  "sensitized. " 

A  further  important  observation  was  made  by  Bordet,  in  1901, 
in  what  is  known  as  "complement  fixation,"  which  since  then  has 
assumed  very  great  practical  importance.  If  we  take  a  bacterial 
emulsion,  say  of  typhoid  bacilli,  and  add  its  inactivated  heated 
immune  serum  (serum  from  a  typhoid  patient)  plus  complement 
(any  normal  serum)  and  then  to  this  mixture  of  antigen-ambocep- 
tor-complement  add  sensitized  red  blood  cells,  i.e.,  red  blood  cells 
with  their  specific,  but  inactivated  serum,  no  hemolysis  will  result. 
If,  on  the  other  hand,  we  take  a  typhoid  bacillary  emulsion  and 
add  normal  serum  plus  complement  and  then  add  to  this  mix- 
ture of  antigen-zero-complement  sensitized  red  blood  cells,  hemo- 


IMMUNITY  117 

lysis  will  take  place.  Plainly,  in  the  first  experiment  antigen  (ty- 
phoid bacilli)  plus  amboceptor,  plus  complement  have  firmly  united 
so  that  complement  is  no  longer  available  for  the  completion  of  the 
added  inactive  hemolytic  system.  In  the  second  case,  antigen  (ty- 
phoid bacilli)  no  amboceptor,  but  only  complement,  the  latter 
remains  free  and  may  then  complete  the  added  inactive  hemolytic 
system.  In  other  words  one  antigen-amboceptor-complement 
combination  fixes  the  complement  firmly  so  that  it  is  no  longer 
available  to  complete  another  added  inactivated  system. 

This  important  discovery  of  complement  fixation  has  since  then 
been  extensively  used  for  diagnostic  purposes,  that  is,  to  test 
whether  a  suspected  serum  contains  a  specific  antibody  or  not. 
The  hemolytic  system  is  introduced  simply  as  a  convenient  color 
indicator.  If  a  patient's  serum  plus  an  antigen  fixes  complement 
so  that  sensitized  blood  cells  which  are  added  do  not  hemolyze,  the 
serum  contains  the  specific  antibody;  the  patient,  therefore, 
passes  or  has  passed  through  the  suspected  disease.  If,  on  the  other 
hand,  the  patient's  serum,  plus  an  antigen,  does  not  fix  complement 
so  that  added  sensitized  red  blood  cells  undergo  hemolysis,  it  is 
plain  that  the  suspected  serum  did  not  contain  the  sought-for 
amboceptor;  the  union  or  fixation  of  complement  is,  therefore,  not 
accomplished  and  it  remains  in  solution  to  unite  with  the  added 
sensitized  red  blood  cells  to  complete  their  antigen-amboceptor- 
complement  hemolytic  system;  that  is,  hemolysis  takes  place. 

Upon  these  observations  rests  the  original  rationale  of  the  Was- 
sermann  reaction  for  syphilis :  Wassermann  took  extracts  of  syphi- 
litic organs  as  a  convenient  way  of  furnishing  antigen,  mixed  these 
with  the  serum  of  a  suspected  case  of  syphilis  in  the  presence  of 
complement,  then,  after  incubation,  added  sensitized  red  cells. 
It  was  found  that  under  those  conditions  syphilitic  serum  fixed 
complement,  that  is,  no  hemolysis  occurred.  Absence  or  occurrence 
of  hemolysis,  as  an  indicator  showed  thus  presence  or  absence  of 
syphilitic  amboceptor  (antibody)  in  suspected  sera. 

There  are  several  points  which  are  plain  from  the  start  in  relation 
to  this  and  similar  reactions.  First,  that  it  is  strictly  quantitative 
so  that  all  reagents  employed,  antigen,  amboceptor  and  comple- 
ment, must  be  quantitatively  titrated  in  order  to  determine  their 


u8  GENERAL  PATHOLOGY 

strength  before  they  can  be  employed  for  reaction.  Secondly,  that 
certain  technical  precautions  must  be  taken  in  order  to  obtain 
reliable  readings.  This  applies  particularly  to  the  interpretation  of 
what  constitutes  a  positive  reaction,  for  there  are  many  cases  in 
which  the  hemolysis  is  only  partial  or  incomplete  and  in  which  it  is 
doubtful  whether  this  is  produced  by  unfixed  complement  or, 
possibly,  by  a  certain  hemolytic  property  possessed  by  the  human 
serum  to  be  tested.  Only  the  straight  cut,  complete  occurrence  or 
absence  of  hemolysis  are  decisive  negative  or  positive  reactions; 
partial  reactions,  i.e.,  partial  hemolysis  (often  indicated  by  one  plus 
or  two  plus  by  laboratory  investigators),  are  not  to  be  regarded 
as  positive  Wassermann  reactions. 

In  order  to  avoid  these  errors  and  to  simplify  the  procedure 
various  modifications  of  the  reaction  have  been  introduced.  It  fol- 
lows that  the  physician  or  surgeon  should  have  some  intelligent 
acquaintance  with  the  technique  and  manner  of  interpretation  of 
the  laboratory  worker  to  understand  and  apply  results  properly. 
These  technical  considerations — important  as  they  are — will  not 
be  further  discussed  here,  for  we  are  now  concerned  with  the  nature 
of  these  reactions,  their  immunological  significance  and  practical 
applications. 

We  have  spoken  of  antigen,  amboceptor  and  complement  as 
though  they  were  definite  chemical  substances  and  reacted  as 
such,  and  indeed,  although  the  nature  of  these  substance  has  always 
been  unknown,  it  was  generally  believed  until  very  recently  that 
the  union  between  antigen,  amboceptor  and  complement  is  a 
definite  chemical  reaction  and  Ehrlich's  well-known  theory  of 
immunity  rests  entirely  on  the  supposition  of  the  chemical  nature 
of  immunity.  But  continued  observations  have  disclosed  facts 
which  have  given  complement  fixation,  generally,  and  the  Wasser- 
mann reaction  in  particular,  a  different  meaning  and  significance. 

In  the  first  place  it  developed,  as  regards  the  Wassermann 
reaction,  that  we  are  not  dealing  with  a  specific  antigen,  antibody, 
complement  union.  For  not  only  syphilitic  organ  extracts,  but 
alcoholic  extracts  of  normal  organs  serve  the  purpose  of  fixing 
complement  in  the  presence  of  syphilitic  amboceptor.  Further 
experiments  disclosed  that  the  essential  substance  or  substances 


IMMUNITY  119 

which  fulfill  the  duties  of  antigen  in  these  extracts  are  lipoids,  very 
complex,  physically  fat-similar  substances,  many  of  which  contain 
N  and  P,  such  as  the  lecithins,  and  that,  as  shown  by  R.  M. 
Walker,  these  lipoids  need  not  even  be  animal,  but  vegetable,  and 
enter,  quite  irrespective  of  their  source,  into  antibody  comple- 
ment fixation.  Moreover,  it  was  found  that  the  fixation  of 
complement  is  accomplished  by  colloidal  substances  like  casein, 
silicic  acid,  barium  sulphate,  etc.,  and  Muir  has  demonstrated  the 
retention  of  complement  by  the  Berkefeld  filter,  through  which 
it  passed  after  a  time  unaltered. 

From  this  and  other  experiments  it  appears  that  fixation  of 
complement  is  influenced  by  the  surface  of  the  substance  to  which 
it  is  fixed  and  that  in  the  organ  extracts  which  are  employed  as 
antigens  the  surface  of  the  suspended  lipoid  particles  plays  an 
important  role  in  this  phenomenon.  Clearly,  we  are  not  dealing  here 
with  chemical  reactions,  but  with  physical  phenomena,  character- 
istic of  colloids,  substances  which  since  the  time  of  Graham  have 
been  recognized  as  large  molecular  complexes  which  exist  in  solu- 
tions either  as  suspensoids  or  emulsoids.  The  antigen  or  antigens 
for  the  Wassermann  reaction  have  then  only  this  in  common,  that 
they  are  colloidal  lipoids,  but  not  one  uniform  chemical  compound. 

It  has  also  been  found  that  the  antibody  or  amboceptor  is  not 
strictly  speaking  a  chemical  entity,  but,  on  the  contrary,  it  seems 
to  be  made  up  of  lipoidal  complexes  in  combination  with  a  proteid 
of  euglobulin  nature  and,  therefore,  also  behaves  as  a  colloid. 
Moreover,  comparative  reactions  of  antigen,  amboceptor,  and  com- 
plement do  not  follow  the  chemical  laws  of  multiple  proportions. 

The  importance  of  this  was  early  emphasized  in  the  technique 
of  the  Wassermann  reaction  by  Noguchi,  and  recent  investigations 
of  R.  M.  Walker  have  further  shown  that  the  union  of  comple- 
ment to  so-called  antigen  and  so-called  antibody  follows  essentially 
the  laws  of  adsorption.  Thus,  when  the  concentration  is  doubled, 
the  amount  adsorbed  does  not  equal  2,  but  less,  namely  to  the 

formula  of  2  to  the  power  ^- 

Taking  all  these  facts  into  consideration  it  is  clear  that  the 
Wassermann  reaction  is  a  colloidal  adsorption  phenomenon  and  no 


120  GENERAL  PATHOLOGY 

chemical  reaction.  It  depends  for  its  occurrence  upon  the  presence 
of  lipoid  proteid  complexes  in  the  serum  of  syphilitics  which,  when 
put  in  contact  with  other  lipoids,  extracted  from  any  lipoid-rich 
organs,  possess  the  ability  to  adsorb  complement. 

What  determines  the  specific  adsorption  and  fixation  of  these 
substances  to  each  other  is  at  present  impossible  to  say.  It  may  be 
said,  as  a  reminder,  that  adsorption  is  essentially  bound  to  surface 
tension,  that  is,  work  may  be  done  by  the  surface  of  a  liquid  when 
the  tension  is  able  to  diminish.  Substances  of  great  chemical  sta- 
bility only  slightly  lower  surface  tension  when  spread  on  water; 
some,  like  ether,  spread  widely  and  greatly  lower  surface  tension. 
Bayliss  suggests  that  this  is  due  to  decomposition  at  the  interface 
between  liquid  and  air  and  between  solution  and  a  solid,  or 
immiscible  liquid.  At  these  interfaces  there  is,  therefore,  a  local 
accumulation  of  free  surface  energy  which  can  be  altered  by  the 
deposit  of  substances  at  the  interface.  From  the  Gibbs-Thompson 
law  of  energetics  it  follows  that  substances  which  lower  surface 
tension  will  be  concentrated  in  this  situation  because  the  energy 
will  be  lessened  thereby.  Accordingly,  any  substance  in  solution 
in  contact  with  the  surface  of  another  phase  will  be  concentrated 
on  that  surface,  if  thereby  the  free  energy  present  is  decreased. 
This  is  adsorption  and  characteristic  in  its  relation  to  surfaces  of 
contact. 

The  exact  conditions  controlling  the  adsorption  of  colloids  are  as 
yet  not  well  known,  nor  are  the  factors  determining  specific  ad- 
sorption in  mixtures.  It  is  possible  that  related  physical  configura- 
tion of  molecular  complexes  are  of  importance  in  this  respect 
and  electrical  relations  of  substances  are  certainly  concerned. 
These  considerations  are  not  only  of  theoretical,  but  great  practical 
importance,  for  the  specificity  of  the  Wassermann  reaction  has 
thereby  been  much  limited.  We  are  enabled  to  understand  now 
better  the  gradually  increasing  number  of  instances  in  which  the 
Wassermann  reaction  is  positive  in  non-syphilitics  and  the  lack 
of  the  reaction  at  times  in  syphilitics. 

As  a  result  of  long-continued  observations  carefully  carried  on 
by  Dr.  Bruere  in  these  laboratories  and  by  other  observers,  it 
may  be  laid  down  as  a  general  proposition  that  agents  which  either 


IMMUNITY  121 

increase  or  diminish  the  lipoid  protein  contents  of  the  blood  may 
interfere  with  the  specificity  of  the  reaction,  rendering  the  results 
of  doubtful  value  as  a  test  for  syphilis.  Under  such  conditions 
positive  reactions  may  occur  which  are  not  necessarily  due  to 
syphilis.  Thus,  during  digestion  (particularly  after  fatty  meals) 
in  acidosis,  lipemia,  and  after  chloroform  or  ether  anesthesia,  the 
blood  may  give  a  strong  positive  reaction  in  non-syphilitics,  be- 
cause lipoids  are  dissolved  and  thrown  into  the  blood  stream. 
On  the  other  hand  it  appears  that  the  reaction  after  long  anesthe- 
sia or  alcoholic  debauch  may  become  negative  in  syphilitics,  pos- 
sibly, because  much  lipoid  has  been  dissolved  out  of  the  blood. 
Thus  also,  the  blood  may  be  negative  and  the  cerebro-spinal  fluid 
positive.  The  same  applies  to  infectious  diseases,  especially  where, 
as  in  pneumonia,  rapid  resorption  of  large  amounts  of  inflammatory 
exudate  occurs,  or  in  ulcerating  tumors.  Here  also  the  blood  be- 
comes rich  in  euglobulin,  which  is  one  of  the  components  of  the 
amboceptor  in  syphilitic  blood  and  lipoids. 

This  very  practical  lesson  must,  therefore,  be  drawn,  that,  in 
order  to  obtain  a  reliable  test  for  syphilis  with  the  Wassermann 
reaction  it  is  necessary  to  use  the  following  precautions:  First, 
blood  must  be  taken  directly  from  vessels,  avoiding  the  skin, 
(subcutaneous  fat),  and  not  by  blister  or  cupping.  Second,  blood 
should  never  be  taken  (a)  after  a  meal  (but  while  fasting),  (6) 
during  a  fever,  (c)  during  any  acute  infectious  disease,  (d)  during 
suppurations  or  resorptions  of  large  inflammatory  exudates  (pueu- 
monia,  empyema,  etc.),  or  even  in  ulcerating  or  necrosing  tumors, 
(e)  after  narcosis. 

As  a  second  proposition,  it  may  be  put  down  that  a  negative 
Wassermann  does  not  necessarily  exclude  syphilis.  The  value  of  the 
Wassermann  reaction  in  the  diagnosis  of  syphilis  should  not  be 
discredited  or  underestimated,  but  our  experiences,  together  with 
those  of  others,  emphasize  the  necessity  of  proper  precautions  in 
obtaining  the  material  (blood)  for  the  reaction.  It  also  explains 
relative  value.  Here,  then,  theoretical  considerations  as  well  as 
practical  results  meet,  and  when  combined  give  us  an  intelligent 
understanding  and  a  reliable  application  of  a  complicated  immu- 
nity reaction. 


122  GENERAL  PATHOLOGY 

The  principles  underlying  the  Wassermann  reaction  have 
a  much  wider  and  general  application  to  immunity.  For  in- 
stance, if  a  given  quantity  of  diphtheria  antitoxine  is  added  to 
the  toxine  in  fractions,  neutralization  of  less  toxine  occurs  than 
when  all  is  added  at  the  same  time. 

This  is  also  true  of  ricine,  the  toxic  principle  of  the  castor  bean, 
and  antiricine.  If  ricine  is  added  in  separate  amounts  to  antiricine, 
more  antiricine  is  necessary  for  neutralization  than  when  all  ricine 
is  added  at  once.  It  has  also  been  shown  in  the  frog  that  adsorption 
of  tetanus  toxine  by  the  nerve  trunk  occurs  at  low  temperature, 
but  poisonous  effects  do  not  occur  until  the  animal  is  heated  to 
2o°C.  Even  the  chemical  specificity  of  the  amboceptor  or  antibody 
in  other  immunity  reactions  is  not  quite  certain.  It  may  represent 
only  an  increased  production  or  rearrangement  of  substances 
normally  present  in  tissues  and  fluids  which  under  certain  condi- 
tions and  influences  form  large  colloidal  complexes  and  by  selective 
adsorptions  pose  as  specific  chemical  compounds  in  their  reactions. 

The  peculiar  successful  treatment  of  certain  diseases  with  non- 
specific proteins,  such  as  joint  infections  with  typhoid  vaccines,  are 
perhaps  to  be  explained  in  this  manner. 

A  similar  phenomenon  is  the  formation  of  precipitines.  If  we 
inject  at  several  sittings  the  serum  of  an  animal  A  into  an  animal  B, 
the  serum  of  the  latter  acquires  the  power  to  precipitate  the  serum 
of  animal  A  and  this  precipitation  appears  to  be  relatively  specific, 
so  that  it  occurs  only  in  high  dilutions  with  the  serum  of  an  animal 
against  which  immunization  has  been  made. 

To  detect  human  blood,  for  example,  it  is  only  necessary  to 
immunize  a  rabbit  or  guinea  pig  against  human  serum;  this  im- 
munized serum  will  then  precipitate  in  high  dilutions  (1:1000 
and  over)  a  human  serum  and  that  of  high  anthropoid  apes  only, 
but  no  other.  This  reaction  has,  therefore,  acquired  great  medico- 
legal  importance.  The  reaction  is  given  also  by  the  serum  in 
human  exudates  and  transudates,  and  slight  reactions  should  not 
be  regarded  as  conclusive,  as  they  are  not  specific.  Moreover,  the 
precipitate  is  redissolved  rapidly  in  low  dilutions  (i  :ioo). 

Agglutination  of  bacteria  follows  essentially  the  laws  of 
hemolysis. 


IMMUNITY  123 

From  what  has  been  presented,  it  appears  that  these  phenomena 
of  immunity  are,  partly,  of  complicated  colloidal  character,  largely 
in  the  nature  of  adsorption,  partly  adsorption  plus  chemical  union 
of  at  present  quite  unknown  substances. 

There  is  another  phase  of  immunity  which  at  first  sight  appears 
far  removed  from  the  Wassermann  reaction,  but  which  careful 
reflection  shows  very  close  relation  to  it,  chemiotaxis  and  phago- 
cytosis. Movement  and  ingestion  of  foreign  particles  such  as  food, 
bacteria  and  pigment  are  fundamental  characteristics  of  life  and 
possessed  by  all  free  cells.  In  higher  animals  the  movement  and 
ingestion  of  foreign  particles  appears  particularly  strong  in  meso- 
dermal  cells,  especially  leucocytes,  but  other,  more  highly  developed 
cells  are  also  capable  of  ingesting  foreign  matter  and  thus  play  an 
important  role  in  consumption  and  removal  of  bacteria.  Thus  Si- 
mon showed  in  a  case  of  cerebro-spinal  meningitis  7,380,000 
organisms  per  c.c.  in  leucocytes.  Wright  and  Douglas  found  that 
phagocytosis  proceeds  better  in  serum,  and  therefore  suggested 
that  this  was  due  to  the  presence  of  substances  in  the  serum  which 
made  bacteria  more  susceptible  to  cell  ingestion;  prepared  them, 
so  to  speak  for  the  leucocytes.  They  termed  these  hypothetical 
substances  opsonins  (from  opsonare  —  to  make  palatable)  and 
observed  that  vaccination  with  killed  cultures  of  bacteria  in- 
increased  the  opsonic  contents,  i.e.,  the  opsonic  index,  of  the 
leucocytes  towards  the  particular  vaccinated  organism. 

These  views,  which  were  at  one  time  very  enthusiastically 
received,  have  been  materially  altered  by  our  recent  more  perfect 
knowledge  of  the  nature  of  chemiotaxis  and  phagocytosis.  Both 
were  once  regarded  as  specific  of  living  forms,  and  in  a  way,  intelli- 
gent expressions  of  life  and  useful  efforts  of  protection.  To-day  we 
know  that  these  functions  are  by  no  means  confined  to  living  cells, 
that  both  properties  follow  essentially  the  laws  of  surface  tension 
in  cells  as  in  non-living  substances  suspended  in  fluid.  When  a 
drop  of  fluid  is  suspended  in  another,  the  particles  of  each  fluid 
are,  as  is  well  known,  under  a  considerable  cohesion  force,  which 
holds  them  together.  Within  the  drop  suspended  in  the  fluid  the 
force  is  equalized  by  each  particle  being  subjected  to  the  same 
pressure  or  force  from  all  sides.  But  the  particles  on  the  surface 


i24  GENERAL  PATHOLOGY 

of  the  drop  are  exposed  to  unequal  pressure,  for  that  of  the  outside 
fluid  is  different  from  that  of  the  drop,  so  that  the  surface  particles 
are  exposed  to  the  pressure  of  the  two  fluids,  and  this  is  surface 
tension.  The  surface  tension  endeavors  to  reduce  the  free  surface 
to  a  minimum  and  this  is  perfectly  represented  by  the  sphere. 

But  the  cohesion  affinity  and  power  varies  in  fluids,  so  that  some 
have  high,  some  low  surface  tension.  Again,  if  substances  are  dis- 
solved one  in  another  the  resultant  surf  ace  tension  equals  that  of  the 
two  substances.  If,  then,  on  a  point  of  the  surface  of  a  drop  sus- 
pended in  another  fluid,  the  tension  is  lowered,  remaining  station- 
ary elsewhere  the  drop  will  bulge  and  flow  in  that  direction.  If, 
on  the  other  hand,  the  surface  tension  is  increased  at  a  given  point, 
the  wall  of  the  drop  will  be  indented,  and  the  whole  drop  will  flow 
away  from  this  increased  tension  towards  less  resistant  parts. 

Thus  we  have  movements  closely  simulating  positive  and  nega- 
tive chemiotaxis.  If,  for  example,  we  take  a  drop  of  metallic  mer- 
cury and  suspend  it  in  a  flat  Petri  dish  in  a  10  per  cent,  solution  of 
HNO3,  the  drop  will  assume  the  shape  of  a  sphere.  Suppose  we  now 
put  a  crystal  of  potassium  bichromate  in  the  solution  close  to  the 
mercury.  As  the  crystal  dissolves  and  strikes  a  point  on  the  surface 
of  the  drop  of  mercury  this  is  oxidized,  the  surface  tension  thereby 
lowered  and  the  drop  projects  in  this  direction,  sends  out  pseudo- 
podia  and  ultimately  moves  towards  the  crystal,  around  which  it 
will  execute  the  most  active  and  bizarre  motions,  apparently 
battling  with  it  until  the  surface  tension  has  again  been  equalized 
by  the  solvent  action  of  the  acid  on  the  oxide;  then  the  mercury 
assumes  once  more  the  quiescent  form  of  a  sphere.  If  we  dissolve 
the  potassium  chromate  first  in  the  acid  water  and  then  add  a  drop 
of  mercury,  the  motions  of  the  drop  are  slower,  more  ameba-Iike. 

This  is,  of  course,  a  very  simple  and,  in  a  way,  crude  experiment, 
but  we  owe  to  Ludwig  Rhumbler  most  interesting  and  elaborate 
observations  which  show,  on  the  assumption  of  the  colloidal 
nature  of  cells,  that  chemiotaxis  and  phagocytosis  are  funda- 
mentally surface  tension  phenomena. 

Ameba,  leucocyte  or  other  cells  are,  physically  considered, 
drops  of  a  colloidal  suspension  surrounded  by  a  delicate  surface 
layer  which  is  more  or  less  readily  permeable  to  solvents  and  sub- 


IMMUNITY  125 

stances  in  solution.  In  any  fluid  such  a  colloid  drop  is  suspended  in 
a  liquid  of  different  composition.  These  conditions  may  be  imitated 
in  a  simpler  fashion  by  suspending  a  drop  of  clover  oil  or  chloroform 
in  glycerol  and  weak  alcohol,  with  which  it  will  gradually  mix. 
Such  a  drop  will  move  about,  send  out  pseudopodia  and  change 
its  form  as  an  ameba  does.  If  some  strong  alcohol  is  added  near 
the  drop,  the  surface  tension  on  this  side  will  be  lowered  and  the 
drop  will  flow  in  that  direction  (chemiotaxis) .  It  will  also  flow  to- 
wards a  heated  point,  because  heat  lowers  surface  tension. 

But  further,  even  the  ingestion  and  choice  of  food  may  beartific- 
ally  produced.  A  drop  of  chloroform  in  water  or  weak  alcohol  will 
refuse  certain  substances,  such  as  glass  or  wood,  and,  if  introduced, 
will  expel  (vomit)  them ;  but  if  a  piece  of  thread  of  shellac,  vulcan 
or  paraffin  be  brought  into  contact  with  it,  the  drop  will,  in  ameba 
fashion,  flow  around  it.  Even  more,  if  a  thread  which  an  ameba 
ingests  is  too  long,  it  stretches  along  the  thread  and,  by  bending  it, 
crowds  the  thread  into  a  coil  within  its  body.  This  looks  like  a 
voluntary  or  instinctive  action,  but  Rhumbler  showed  that  when  a 
long  thread  of  shellac  is  offered  to  a  drop  of  chloroform,  it  proceeds 
to  bend  the  thread  in  the  middle,  sends  out  pseudopodia  along 
the  thread  to  pull  it  in,  coils  it  up  inside  and  then  digests  it.  A 
thread  six  times  as  long  as  the  drop  of  chloroform  may  thus  be 
taken  in.  Moreover,  if  a  piece  of  glass  rod  is  covered  by  shellac  and 
then  introduced  into  the  chloroform  drop,  the  shellac  is  retained, 
but  the  glass  rod  expelled. 

Even  the  formation  of  shells  by  certain  protozoa  (difflugia)  has 
been  imitated  by  Rhumbler  by  mixing  oil  with  quartz  grains  and 
70  per  cent,  alcohol.  The  grains  are  thrown  out  to  the  surface  of 
the  oil  drops  and  adhere  to  one  another  as  they  do  in  difflugia,  and 
these  artificial  shells  remain  intact  for  months.  While  the  ameba 
and  other  cells  are  certainly  much  more  complicated  in  their  make- 
up and,  therefore,  in  their  physical  relations  to  the  outside,  these 
experiments  strongly  suggest  that,  at  least,  many  of  the  elementary 
motions  and  actions  of  cells  are  exhibitions  of  changes  in  surface 
tension.  This  is  also  borne  out  by  the  observations  on  the  behavior 
of  higher  tissue  cells  towards  certain  reagents.  Thus,  B.  Fischer 
found  that  the  injection  of  Sudanor  scarlet  red  in  oil  into  the  ear 


126  GENERAL  PATHOLOGY 

of  rabbits  caused  dissociation  of  the  surface  epithelium,  and  growth 
and  migration  towards  the  Sudan.  The  same  influence  has  been 
found  after  the  application  of  coal-tar,  ether,  and,  generally  speak- 
ing, lipoid  solvents,  as  also  in  artificial  parthenogenesis  by  J.  Loeb. 

The  term  chemiotaxis  is,  therefore,  strictly  not  correct,  for  the 
attraction  of  cells  does  not  depend  upon  chemical  affinity,  as  once 
believed,  but  upon  physical  changes  in  the  environment  of  cells. 
It  is  probable  that  the  emigration  of  leucocytes  in  inflammatory 
exudation  depends  upon  the  same  phenomena  for  the  products  of 
cell  disintegration,  and  inflammatory  irritants  lower  surface  tension 
in  the  tissue  fluids.  When  these  diffuse  into  the  blood  they  will  nec- 
essarily attract  leucocytes  in  the  direction  of  the  greatest  lower- 
ing of  the  tension.  They  pass  then  through  stomata  of  vessels  and 
move  in  the  tissue  fluids  until  the  tension  is  once  more  equalized. 

The  changes  in  size  and  shape  of  inflammatory  cells  after  exuda- 
tion, their  polymorphous  character  and  the  fusion  of  cells  to  giant 
cells  are  also  largely  governed  by  the  physical  factors  of  their 
environment.  If  we  take  small  particles  of  camphor  and  throw  them 
into  water,  they  exhibit  very  active  motion.  If  we  now  cover  the 
surface  of  the  water  by  a  thin  film  of  oil  and  thus  equalize  surface 
tension,  the  camphor  particles  come  together,  agglutinate  and 
form  large  irregular  masses  such  as  occurs  in  cell  agglutination 
and  cell  fusion.1 

We  may,  therefore,  conclude  that,  as  the  Wassermann  reaction 
depends  upon  phenomena  of  surface  energy  (adsorption)  so 
depend  chemiotaxis  and  phagocytosis  upon  phenomena  of  surface 
tension.2  It  is  clear,  therefore,  that  what  was  called  opsonins 
and  opsonic  differences  are  essentially  not  chemical,  but  physical 
phenomena. 

NATURAL  IMMUNITY.  At  the  beginning  it  was  stated  that  the 
third  phase  of  immunity,  the  goal  of  desirable  immunity,  is  the 
creation  of  conditions  which  are  unfavorable  to  settlement  and 
growth  of  infecting  agents  by  modifying  the  physical  and  chemical 
constitution  of  tissues.  We  have  known  for  a  long  time  that  individ- 

1  See  later  under  Inflammation. 

2  It  may  be  readily  conceded  that  these  phenomena  show  in  living  cells  cer- 
tain modifications,  but  these  are  not,  as  far  as  I  can  see,  fundamental  differences. 


IMMUNITY  127 

uals  may  carry  after  an  infection,  or  even  never  having  undergone 
any  infection,  virulent  bacteria,  and  these  individuals,  so  important 
from  the  epidemiological  standpoint,  are  spoken  of  as  of  "carriers. " 

Instructive  in  this  regard  is  especially  gonorrhea.  For  we  know 
that  the  gradual  adaptation  of  the  gonococcus  to  the  urethral 
mucous  membrane  is  not  due  to  any  bactericidal  action  of  the 
tissues,  but  that  the  gonococcus  continues  fully  virulent  and  that, 
therefore,  the  inflammation  excited  by  this  irritant  does  not  heal 
by  annihilation  or  even  decreasing  the  virulence  of  the  invading 
agent.  We  also  know  that  venous  congestion,  although  in  other 
respects  rather  detrimental  to  cell  life  by  asphyxia  and  increased 
H  ionization  of  the  tissues,  is  unfavorable  to  settlement  and  growth 
of  bacteria.  Bier's  famous  treatment  of  tuberculosis  depends  on  this 
observation.  How  can  these  perplexing  questions  be  explained?  It 
would  seem  that  here  also  complex  physico-chemical  conditions  of 
the  tissues  are  involved  which  make  an  attack,  or  better  expressed, 
a  union  of  bacteria  to  cells  impossible. 

It  appears,  from  recent  observations  in  which  Dr.  Gross  and 
the  author  are  still  engaged,  that  the  colloidal  state  of  cells  and 
their  physical  environment  are  of  great  importance  here.  We 
have  deviated  in  our  studies  of  natural  immunity  from  the  general 
custom  of  employing  complex  animals,  and  have  chosen  the  simplest 
kind  of  protozoal  organism,  the  paramecium,  for  our  studies.  This 
we  have  been,  and  are  still  growing  under  varying  physical  in- 
fluences with  pathogenic  bacteria.  We  have  observed  that  the 
ability  of  pathogenic  bacteria  to  attack  and  destroy  paramecia 
depends  to  a  considerable  extent  upon  physical  factors,  such  as 
salt  contents  of  the  media;  that,  for  example,  in  higher  salt  con- 
centrations paramecia  are  more  vulnerable  than  in  lower  or  saltless 
media  (swelling  and  hydrops  of  cells).  These  studies  are  not  yet 
sufficiently  completed  to  draw  definite  conclusions,  but  they  are 
suggestive  of  the  importance  of  physical  factors  in  infection. 

It  is  possible  that  the  interesting  recent  observations  of  Cramer 
and  Bullock  belong  to  the  same  category.  By  injection  of  various 
substances  such  as  calcium  salts  and  gelatine,  they  produced  what 
they  term  kataphylaxis  or  local  break  of  tissue  defense.  Organisms 
like  the  bacteria  aerogenes  or  tetanus  bacillus,  which  under  ordinary 


I28  GENERAL  PATHOLOGY 

conditions  are  non-pathogenic,  may,  by  such  a  local  break  of  tissue 
defense,  acquire  virulent  properties.  Bullock  and  Cramer  attribute 
this  "defense  break"  to  disturbance  in  vascular  and  lymphatic 
drainage  from  injury,  but  in  view  of  what  has  been  presented  here 
this  effect  may  be,  at  least  partly,  of  physical  nature  by  creation 
of  conditions  which  allow  interaction  between  micro-organisms 
and  cells  and  thereby  disease. 

PASSIVE  IMMUNITY.  The  immunity  which  we  have  so  far 
considered  is  an  active,  anti-infectious  immunity,  that  is,  one  in 
which  the  immunity  depends  upon  reactions  between  the  body 
cells  and  the  invading  agent.  Intimately  connected  with  it  is  the 
active,  antitoxic  immunity  in  which  cells  produce  substances 
which  enter  into  union  with  bacterial  products  and  thereby  neu- 
tralize or  immobilize  specific  bacterial  poisons,  for  example,  the 
toxines  secreted  by  the  diphtheria  or  tetanus  bacillus. 

These  antitoxines,  the  nature  of  which  is  still  quite  obscure,  are 
products  of  tissue  cells,  and  are  poured  into  the  serum  of  infected 
animals  in  excess  so  that  animals  (horses,  for  instance)  may  then 
receive  100  to  300  times  the  fatal  dose  without  fatal  results. 
Behring  (see  Diphtheria)  showed  that  by  artificial  immunization 
of  animals  against  diphtheria  the  immunity  could  be  transferred 
to  others  by  injection  of  the  immune  serum.  The  second  animal  is 
thus  passively  immunized;  that  is,  without  any  action  of  its  own 
cells  it  enjoys  the  work  of  the  first  animal. 

This  passive  immunity,  however,  is  never  as  lasting  as  an  active 
one — at  the  longest  only  several  months,  but  its  advantages  are 
immediate  and  prophylactic.  Passive  or  antitoxic  immunity  is 
limited  to  specific  esotoxines,  and  cannot  be  employed  with  success 
against  endotoxines.  In  the  discussion  of  diphtheria  toxine  and 
antitoxine  our  knowledge  and  the  principles  of  toxine  and  anti- 
toxine  reactions  has  already  been  made  known.  A  curious  pheno- 
menon occasionally  observed  in  animals  with  a  very  high  antitoxine 
content  of  their  blood  is  the  so-called  paradox  reaction,  in  which 
the  immunized  animal  becomes  again  susceptible  to  toxine  action. 
Its  cause  is  unknown.  Some  suppose  that  a  very  large  antitoxine 
content  of  the  blood  injures  tissue  cells  and  thus  makes  them  once 
more  susceptible  to  toxine;  then,  again,  it  may  be  that  union 


IMMUNITY  129 

(adsorption)  of  the  colloidal  antitoxine  and  toxine  complexes  is 
possible  only  within  certain  quantitative  limits. 

ANAPHYLAXIS:  (From  &v&<pv!;is  =  unguarded).  It  has  long 
been  recognized  that  while  certain  diseases  confer  immunity, 
others  leave  a  patient  either  unprotected  or  in  some  instances  even 
more  susceptible.  As  early  as  1874  Dallera  noticed  peculiar  skin 
eruptions  following  transfusion  of  blood.  In  1902  Richet,  after  he 
with  Hericourt  had  observed  in  1898  toxic  effects  in  dogs  from 
repeated  injections  of  eel  serum,  found  that  intravenous  injection 
of  a  non-fatal  dose  of  extracts  of  tentacles  of  actiniae  produced,  if 
repeated,  serious  results.  The  animals  so  treated  died.  Thus, 
0.08  c.c.  was  used  in  the  first  injection  without  bad  effects,  while 
o.ooi  in  the  second  injection  at  once  caused  serious  effects.  The 
animal  was,  therefore,  on  second  injection,  80  times  more  sus- 
ceptible than  on  the  first.  The  first  injection  had,  in  some  way, 
rendered  the  animal  hypersusceptible.  Hence  the  name  anaphy- 
laxis  =  absence  of  protection. 

It  was  later  found  that  similar  symptoms  occurred  after  re- 
peated injections  of  horse  serum  and  ordinarily  non-toxic  sub- 
stances (Arthus).  If,  for  example,  a  rabbit  was  injected  with  horse 
serum,  a  single  injection  would  be  sufficient  to  cause,  on  repetition, 
even  with  a  smaller  dose,  alarming  symptoms.  This  is  known  as 
serum  sickness.  Theobald  Smith  noticed  similar  phenomena  in 
guinea  pigs  employed  for  the  standardization  of  diphtheria  anti- 
toxine. If  reinjected  with  horse  serum  about  50  per  cent,  died  with 
symptoms  of  dyspnea,  feeble  heart  action  and  drop  in  temperature. 

The  smallness  of  the  second  dose  necessary  to  produce  this  so- 
called  anaphylactic  shock,  and  the  rapidity  of  its  occurrence  are 
sometimes  remarkable.  The  reaction  appears  to  be  specific  to 
the  substance  originally  employed  and  may  be  transferred  by  the 
serum  to  another  animal  of  the  same  species.  It  also  appears  that 
this  hypersensitiveness  is  transmitted  from  mother  to  offspring, 
at  least  in  guinea  pigs. 

A  definite  period  must  always  elapse  between  the  first  and 
second  injection  in  order  to  obtain  toxic  manifestations.  In  sensi- 
tizing guinea  pigs  against  horse  serum,  for  example,  ten  to  twelve 
days  must  intervene  between  the  two  injections  (Rosenau  and 


i3o  GENERAL  PATHOLOGY 

Anderson).  Sometimes  very  small  first  doses  are  sufficient  to 
hypersensitize.  Rosenau  and  Anderson  sensitized  a  guinea  pig 
with  M»ooo-ooo  c-c-  of  horse  serum,  but  then  the  second  dose 
must  be  much  larger  to  cause  effects,  }{Q  c.c.  and  even  3  to  6  c.c. 
to  kill.  The  reaction  is  extremely  delicate  and  Wells  has  detected 
0.000,001  gm.  of  a  protein  by  it.  Certain  it  is  that  the  individual 
anaphylactic  susceptibility  varies,  even  in  the  same  species. 

The  nature  of  anaphylaxis  is  not  quite  clear.  It  is  certainly  an 
immunity  reaction,  and  is,  in  the  opinion  of  Vaughan  and  others, 
to  be  explained  on  the  basis  of  what  occurs  in  infection  and  paren- 
teral  introduction  of  proteins.  We  have  already  touched  upon  this  in 
consideration  of  infection.  Accordingly,  anaphylaxis  depends  upon 
an  enzyme  produced  by  the  body  cells  as  a  result  of  the  stimu- 
lating effect  of  a  parenterally  introduced  protein  (time  necessary 
to  produce  the  anaphylactic  shock  is  considered  the  time  necessary 
to  furnish  the  enzyme).  This  enzyme  splits  the  foreign  proteid  and 
sets  free  the  central,  poisonous  chemical  nucleus  which  then 
intoxicates.  The  rapidity  and  severity  of  this  shock  after  minimal 
doses  is,  however,  not  made  intelligible  by  this  explanation,  as  well 
as  its  peculiar  symptom  complex  which  differs  from  that  of  infec- 
tious endotoxine  poisoning,  both  of  which,  according  to  this  con- 
cept, would  be  essentially  of  the  same  nature. 

The  older  idea  of  Ehrlich,  which  is  to-day  no  longer  held,  rested 
on  his  side  chain  theory  (see  later).  In  his  opinion  cells  enter  into 
relation  with  substances  by  specific  receptors.  He  believed  that 
the  introduction  of  any  toxic  foreign  body  injured  the  receptors, 
but  also  stimulated  the  body  cells  to  the  production  of  new  recep- 
tors with  which  the  toxine  could  enter  into  further  chemical  union 
(see  Theories  of  Immunity).  These  receptors  in  the  case  of  toxine 
are  the  amboceptors  or  antitoxine  and  are  after  a  time  dislocated 
from  the  cell  and  thrown  into  the  blood,  where  they  circulate  and 
are  in  position  to  combine  with,  and  fix,  the  toxine;  bind  it,  there- 
fore, before  it  can  reach  and  attack  the  cell.  In  his  opinion  the 
anaphylactic  shock  occurred  during  that  period  in  which  the  am- 
boceptors are  still  attached  to  the  cells  and  therefore  make  it 
really  more  vulnerable  to  a  toxine  by  offering  a  multiplied  oppor- 
tunity of  entrance  into  the  cell. 


IMMUNITY  131 

Inasmuch  as  Ehrlich's  conceptions  of  immunity  have  lost  much 
support  in  their  general  application  to  the  nature  of  immunity, 
this  hypothesis  of  anaphylaxis  has  been  largely  superseded  by  the 
experimentally  well-established  theory  of  protein  intoxication  of 
Vaughan.  But  even  this  leaves,  as  pointed  out  above,  some  matters 
obscure  and  unaccounted  for. 

Quite  different  is  the  conception  of  Besredka,  who  regards  ana- 
phylaxis as  due  to  a  cumulative  sudden  reaction  between  antigen 
and  antibody  (sensibilism)  which  is  attached  to  the  cells  of  the 
central  nervous  system,  causing  disruption  in  these  cells.  In  other 
words  he,  and  so  do  Gay  and  Southard,  believes  in  a  primary  vul- 
nerability of  cells  and  does  not  see  in  anaphylaxis  a  toxic  antigen 
antibody  reaction.  Moreover,  an  anti-anaphylaxis  may  be  estab- 
lished through  desensitizing  with  minimal,  sublethal  doses  and 
rectal  administration  of  antigen.  Pearce  and  Eizenbrey  showed  that 
a  sensitized  dog  remained  sensitized  even  when  his  entire  blood 
volume  was  substituted  by  that  of  a  normal  dog.  Whatever  the 
nature  of  anaphylactic  poisoning,  its  effects,  if  not  fatal,  pass  off 
quickly,  disappearing  generally  in  a  few  hours.  In  this  respect 
the  action  is  similar  to  that  of  alkaloids. 

The  most  characteristic  and  constant  anatomical  lesion  seems 
to  occur  in  smooth  muscle  (Schultz).  Auer  and  Lewis  observed 
total  asphyxiation  by  spasm  of  the  musculature  of  the  bronchioles. 
This,  however,  does  not  seem  to  be  of  central  origin.  Blood  pressure 
falls.  It  cannot,  however,  be  definitely  stated  whether  there  exists 
a  specific  anaphylotoxine  or  whether  the  whole  symptom  complex 
results  from  proteid  precipitation  or  another  interference  with 
the  colloidal  state  of  cells.  Thus,  Jobling  found  that  intravenous 
injections  of  "Kaolin,"  fine  fossilized  shell  powder,  produces  a 
picture  resembling  anaphylaxis,  in  other  words,  precipitated  and 
finely  divided  particles  might  attach  themselves  to  cells  and  inter- 
fere with  their  functions.  It  is  reasonably  certain  that  the  sub- 
stance or  property  responsible  for  anaphylaxis  is  in  the  body  of 
the  host  and  not  in  the  antigen. 

The  phenomena  of  anaphylaxis  indicate  that  inasmuch  as  the 
parenteral  ingestion  of  proteids  is  much  more  dangerous  than  the 
enteral,  some  steps  occur  in  the  normal  enteric  digestion  which  are 


i32  GENERAL  PATHOLOGY 

omitted,  exaggerated,  or  perverted  in  parenteral  or  direct  intro- 
duction into  the  blood  stream.  Here  the  question  arises  whether 
this  is  a  simple  omission  of  a  detoxicating  step  in  digestion,  or 
whether  the  introduction  of  foreign  particles  into  the  blood 
stimulates,  as  Gideon  Wells  suggests,  the  animal  to  acceleration  of 
this  digestion  with  production  of  toxic  proteolytic  products,  or, 
whether  as  Heilner  believes,  parenteral  sensitization  depresses  the 
normal  annihilation  of  poisonous  proteolytic  substances. 

Interesting  is  the  fact  that  the  excessive,  constant  enteric  con- 
sumption of  large  quantities  of  proteids  is  liable  to  cause  body 
injury;  in  the  opinion  of  some,  definite  disease  (Nephritis). 

A  satisfactory  theoretical  explanation  of  anaphylaxis  is  at  pres- 
ent impossible,  as  experimental  results  are  often  contradictory  and 
their  interpretations  still  differ  widely.  But  the  conception  of  ana- 
phylaxis has  been  extended  to  include  and  account  for  many 
individual  susceptibilities  to  foreign  proteins  and  some  other  sub- 
stances which  are  ordinarily  well  tolerated,  for  example,  intoxica- 
tions after  eating  shellfish,  strawberries,  etc. 

Very  interesting  and  important  is  the  possible  relation  of  the 
anaphylactic  shock  to  some  sudden,  otherwise  inexplainable, 
deaths  in  infectious  diseases  during  convalescence  in  cases  in  which 
resorption  of  large  amounts  of  exudate  occurs.  Such  sudden  deaths 
are  seen  after  crisis  in  pneumonia,  when  the  patient  is  apparently 
on  the  road  to  recovery.  It  is  conceivable  that  the  sudden  heart 
paralysis  in  these  cases  may  be  toxic  from  resorption  of  large 
quantities  of  exudate  and  foreign  proteids  (this  may  amount  to 
as  much  as  2  liters) .  Evidence  is  accumulating  that  certain  obscure 
diseases  such  as  asthma,  hay  fever  (through  pollen  inhalation), 
many  skin  diseases  such  as  urticaria,  eczema,  etc.,  are  of  anaphy- 
lactic origin.  In  one  case  of  asthma,  studied  in  our  laboratories  by 
Bruere,  there  existed  strong  susceptibility  towards  cat's  hair,  and 
a  positive  skin  reaction  (reddening  and  swelling)  was  obtained  by 
vaccination  with  epidermal  extracts,  demonstrating  the  reaction 
of  the  body  against  this  type  of  foreign  protein. 

Closely  related  to  anaphylaxis  is  the  so-called  "allergic"  of  von 
Pirquet.  This  represents  an  altered,  often  attenuated,  reaction 
to  a  virus  after  previous  infection.  (See  Tuberculin  Reactions.) 


IMMUNITY  133 

THEORIES  OF  IMMUNITY.  This  short  review  of  the  principal 
immunity  reactions  has  shown  us  a  multitude  of  diverse  processes 
and  phenomena:  some  poisonous  substances  are  neutralized,  others 
increased  in  toxicity,  and  certain  harmless  substances,  like  ordi- 
nary proteins,  become,  when  parenterally  introduced,  highly 
poisonous.  It  is  not  to  be  wondered  at  that  such  complicated  and 
for  the  most  part  only  little  understood  and  divergent  reactions, 
occurring  between  substances  of  hypothetical  or  entirely  unknown 
constitution  and  of  hazy  conception,  defy  exact  interpretation  and 
explanation. 

There  exist  to-day  two  main  currents  of  thought  for  the 
theoretical  general  explanation  of  immunity.  The  first,  and  older, 
is  purely  chemical,  the  second,  physico-chemical.  The  first  finds 
its  most  perfect  expression  in  the  views  of  Ehrlich  and  his 
followers.  It  has  always  been  attractive,  because  it  offers  a 
visual,  one  might  say,  anatomical,  explanation  of  cell  life  and 
relation  to  its  environment. 

Ehrlich's  studies  with  diphtheria  toxine  and  antitoxine  led  him 
to  regard  toxine  and  antitoxine  as  chemical  compounds  which 
possess  chemical  anchors  (haptophores),  with  affinity  for  corre- 
sponding chemical  receptors  of  the  cells  (simile  to  lock  and  key). 
Thus,  cell  constitution  may  be  compared  to  the  structure  of  the 
benzol  ring  which  by  side  chains  enters  into  chemical  union  with 
other  substances,  although  its  chemical  nucleus  remains  un- 
changed. Just  so  in  Ehrlich's  conception,  the  cell  has  a  stable 
central  constitution  which  by  open  side  chains  communicates  with 
the  outside  world.  Toxines  by  their  chemical  affinity  to  certain  cell 
side  chains  attach  themselves  to  these  receptors  and  thus  enter, 
injure  or  kill  the  cell. 

If  the  cell  is  not  killed,  regeneration  of  the  eliminated  receptors 
occurs,  and,  possibly,  under  the  stimulating  influence  of  the  toxine, 
in  larger  numbers  than  originally.  Ehrlich  borrowed  this  idea  from 
Weigert's  general  principle  of  cell  regeneration  after  injury,  namely, 
that  "regeneration  occurs  always  in  excess  of  the  actual  demand." 
The  excessive  receptors  are  finally  thrown  off  from  the  cells  and 
circulate  in  the  blood  as  amboceptors  (antibodies)  or  antitoxines. 
These  free,  floating  receptors  bind,  therefore,  the  toxine  before  it 


134  GENERAL  PATHOLOGY 

reaches  and  injures  the  tissue  cells,  and  save  the  cells.  The  whole 
immunity  process  is,  according  to  Ehrlich,  only  a  phase  of  general 
cell  activity.  The  assimilation  of  foodstuffs  is,  for  example,  carried 
on  in  similar  side  chain  fashion,  without,  of  course,  injury  to  cell 
and  receptors. 

The  ideas  of  Ehrlich  can  in  their  entirety  no  longer  be  maintained, 
since  we  know  that  immunity  processes  are  not  only  chemical,  but 
essentially  physical,  colloidal  phenomena.  Thus  we  have  seen  that  in 
complement  fixation,  adsorption,  in  chemiotaxis  and  phagocytosis, 
surface  tension,  are  of  paramount  importance,  and  that  reactions 
between  toxine  and  antitoxine,  in  fact  all  immunity  reactions,  re- 
solve themselves  largely  into  physical,  colloidal  and  electrical 
relations. 

Bacteria  exist  in  body  fluids  as  suspensions,  varying  in  disper- 
sity  according  to  their  kind.  They  are  precipitated  by  definite 
amounts  of  electrolytes,  as  suspensions  generally  are.  They  are  not 
precipitated  by  kations  of  alkalies  or  light  metals,  but  by  kations 
of  heavy  metals  and  acids.  Thus  agglutination  of  bacteria  and 
precipitation  of  foreign  proteins  follow  the  rules  of  precipitation 
of  colloids  by  electrolytes.  Ordinarily  the  bacterial  sols  are  some- 
what protected,  like  other  suspensoids,  by  emulsoids.  But  this 
protection  is  less  in  bacteria  than  in  other  suspensoids  and  appar- 
ently is  destroyed  by  the  immune  serum.  In  other  words,  the  immune 
serum  makes  bacteria  more  sensitive  to  the  action  of  electrolytes.  Bordet 
showed  many  years  ago  that  agglutination  of  bacteria  does  not 
occur  when  bacterial  suspensions  and  the  immune  serum  are  freed 
from  NaCI,  but  will  occur,  if  this  is  subsequently  added.  Then  also 
the  rate  of  agglutination  depends  upon  the  concentration  of  the 
suspension  and  electrolytes  and  varies  with  the  valence  of  kations. 
There  is  an  "optimum"  of  precipitation  at  a  definite  ratio  of 
bacteria  sols  to  agglutinin  and  no  precipitation  occurs  in  excesses 
of  either.  This  corresponds  to  precipitations  of  positive  and  nega- 
tive sols ;  moreover,  agglutination  occurs  not  only  between  sols  of 
opposite  electric  charge,  but  with  both.  The  investigations  of 
Biltz  support  the  idea  that  agglutination  rests  essentially  upon 
the  formation  of  adsorption  compounds  and  he  showed  that  the 
distribution  of  "agglutinin" — between  bacteria  and  immune 


IMMUNITY  135 

serum  follows  the  adsorption  law.  (See  Walker's  observations  in 
regard  to  complement  fixation  above.) 

The  difficult  question  in  regard  to  bacterial  adsorption  or  agglu- 
tination is  the  apparent  specificity  of  the  reaction,  that  is,  sols  of 
bacteria  are  generally  affected  only  by  their  immune  serum.  It  is, 
therefore,  argued  that  this  must  be  due  to  a  specific  immune 
substance  in  the  serum  of  immunized  animals. 

However,  it  is  possible  to  simulate  such  specific  reactions  with 
some  common  substances  (emulsoids):  gelatine,  for  example, 
agglutinates  typhoid  and  cholera  bacilli.  That  makes  it  possible 
that  specificity  is  only  due  to  new  physical  conditions,  allowing 
certain  emulsoids,  or  electrolytes  of  the  serum  to  enter  into  con- 
tact with  bacteria.  Moreover,  even  this  so-called  specificity  appears 
more  relative  than  absolute.  Particularly  interesting  here  are  ob- 
servations by  Michaelis  who  showed  an  analogy  between  specific 
agglutination  and  the  optimum  concentration  of  H  ions  for 
precipitation  of  proteins.  This  latter  is  constant  and  characteristic 
for  each  protein  and  also  for  agglutination  of  bacteria  by  acids. 
This  acid  agglutination  is  quite  specific  for  bacteria,  so  that  it  is 
possible  to  distinguish  between  typhoid  bacilli  agglutinated  by  a 
H  ion  concentration  of  4  to  8  X  io~5,  and  the  paratyphoid,  agglut- 
inated by  a  H  ion  concentration  of  1 6  to  32  X  io~5.  Colon  bacilli 
are  not  agglutinated  by  acids. 

Here,  as  in  agglutination  by  specific  sera,  occur  variations 
in  agglutination  phenomena  in  strains  and  through  age  and 
derivation  of  bacterial  cultures. 

Moreover,  Forssner  and  others  have  recently  shown  that 
immunization  of  rabbit's  serum  against  sheep  cells  may  be  accom- 
plished by  other  proteid  organ  extracts  from  different  animals, 
so  that  the  specificity  is  rather  one  against  a  proteid  kind  than 
against  biologic  individuality. 

Thus  as  we  advance  in  our  knowledge,  it  is  revealed  that  the 
multitude  of  phenomena  oj  immunity  are  not  due,  as  was  origin- 
ally supposed,  to  the  appearance  of  new  chemical  individuals  for 
each  reaction  but  to  different  expressions  of  general  physical 
laws  of  colloidal  relations.  The  very  act  of  infection  is  ulti- 
mately traceable  to  them.  For  the  possibility  of  contact  with,  and 


i36  GENERAL  PATHOLOGY 

entrance  of  a  foreign  substance  (bacteria  or  poison)  into,  cells  de- 
pend upon  the  physical  constitution  of  cell  protoplasm  and  of  its 
environment.  These  physical  reactions  of  colloids  and  electrolytes 
are  summary  expressions  (so-called  laws)  of  biological  occurrences ; 
they  do  not,  however,  furnish  a  final  explanation  of  these  processes. 

If  we  review  all  our  present  knowledge  of  infection  and  im- 
munity, we  must  confess  that  much  remains  hidden,  entirely  un- 
known. In  the,  unfortunately  too  one-sided,  investigations  and 
conceptions  of  immunity  to  which  attention  was  drawn  at  the 
beginning  of  this  chapter  the  weight  has  been  placed  entirely  on 
antagonistic  interactions  between  invader  and  host.  On  one  side, 
virulence  and  invasive  power  have  been  entirely  centered  in  bacteria 
and  their  toxines;  on  the  other  side,  protective  immunity  has  been 
entirely  centered  in  reactions  of  the  host  against  bacteria  and 
toxine. 

But  no  one  who  has  carefully  observed  infections  and  immunity 
reactions  in  animals  and  man  can  have  failed  to  be  impressed — all 
conditions  being  equal — with  the  tremendously  important  individ- 
ual specificity  in  bacterial  susceptibility,  virulence  and  presence 
or  absence  of  protective  immunity.  What  accounts  for  these 
phenomena?  We  are  justified  in  inquiring  into  the  possibility  of  re- 
actions by  the  host  to  an  invasion  which  may  benefit  and  augment 
the  actions  of  the  invader;  and  again,  reactions  in  the  invader  on  a 
particular  soil  which  may  limit  and  antagonize  its  own  virulence 
and  existence. 

In  other  words,  may  susceptibility  to,  and  virulence  of,  an  infec- 
tion not  rest  on  a  much  broader  basis  than  we  have  so  far  conceded, 
or  even  carefully  considered?  Future  research  must  decide  just 
how,  and  how  far. 


SECTION  TWO 

PHYSICAL  AND  CHEMICAL  FACTORS 
AS  THE  CAUSE  OF  DISEASE 

CHAPTER  XXIII 
TEMPERATURE— HEAT  AND  COLD 

HEAT.  Temperatures  higher  than  usual  may  affect  the  animal 
organism  either  locally,  in  burns,  scalding  or  combustion,  or 
generally  in  the  action  of  hot  atmosphere  on  the  whole  organism. 

Local  Results.  A  moderate  rise  of  temperature  from  the  nor- 
mal to  40°C.  and  even  slightly  above  it  is,  at  least  for  a  time, 
quite  well  stood  by  tissues.  It  accelerates  functions  and  move- 
ment and  phagocytosis  in  leucocytes  (fever).  But  at  about  5O°C. 
tissues  are  distinctly  injured.  Leucocytes  lose  their  motion,  be- 
come rigid  and  disintegrate.  In  the  red  blood  cells  peculiar  nodular 
projections  appear  (crenation).  These  are  later  detached  and  dis- 
charged into  the  plasma.  At  6o°C.  the  hemoglobin  is  discharged 
and  hemolysis  occurs.  At  7O°C.  tissues  solidify  through  coagulation 
of  cell  proteins.  Still  higher  temperatures  produce  what  is  collect- 
ively called  a  burn. 

Burns,  which  most  frequently  affect  the  surface  of  organs, 
especially  the  skin,  exhibit  various  degrees  of  severity.  Taking 
the  skin  as  an  example  they  give  rise  to :  (i)  Hyperemia  in  vessels 
and  reddening  of  the  skin;  (2)  serous  discharge  (exudate)  from  the 
blood  vessels  into  the  superficial  tissues,  lifting  them  above  the 
surface  (blister);  (3)  necrosis,  death  of  tissues;  (4)  actual  burning 
or  carbonization. 

The  severity  and  results  of  burns  depend  upon  the  degree  of 
temperature,  the  length  of  exposure  and  the  extent  of  the  burn. 
Very  extensive  burns,  even  if  not  severe,  lead  to  great  pain  (periph- 
eral sensory  nerve  irritation)  nervous  shock,  unconsciousness  and 

137 


i38  GENERAL  PATHOLOGY 

coma.  The  body  temperature  is  lowered  as  result  of  increased  heat 
dissipation  (from  hyperemia)  while  the  heat  generation  is  low- 
ered by  the  shock.  An  important  feature  after  severe  and  exten- 
sive burns  is  hemolysis  of  red  blood  cells.  Thus  hemoglobinuria  or 
bloody  urine  results.  The  cause  of  this  interesting  phenomenon 
is  not  clear,  but  it  is  assumed  that  the  disintegration  of  cells  and 
proteins  is,  possibly  through  enzyme  production,  concerned  in  it. 
Even  extensive  burns,  however,  may  heal,  sometimes  with  exces- 
sive scar  formation  and  disfiguring  contraction.  From  these  malig- 
nant tumors  may  arise  as  long  as  50  years  after  the  burn.  It  is  still 
stated  that  a  large  number  of  deaths  from  burns,  if  not  due  to 
immediate  or  remote  shock  or  blood  destruction,  result  from  per- 
forating duodenal  ulcer.  This  statement  is  certainly  much  exag- 
gerated and  its  accuracy  has,  in  recent  years,  been  questioned. 
This  cause  of  duodenal  ulcer  was  attributed  to  vascular  coagulation 
resulting  from  liberation  of  fibrin  ferment  set  free  by  burned  cells. 
Its  occurrence  in  the  duodenum  was  not  satisfactorily  explained. 
2.  General  Results.  The  general  effects  of  hot  atmospheres 
on  the  animal  body  are  spoken  of  as  sun-  or  heat-stroke.  Both 
are  somewhat  different  in  nature. 

1 .  Sunstroke,  takes  place  through  the  direct  effects  of  the  sun's 
rays,  that  is,  the  light  rays  of  the  spectrum  on  the  central  nervous 
system,  especially  the  brain  (field  workers,  soldiers).  It  is  known 
as  insolation.  In  such  cases  autopsy  discloses  hyperemia  and  venous 
congestion  of  brain  and  meninges,  occasionally  with  edema.  This, 
if  the  individual  survives,  may  be  followed  by  meningitis,  probably 
from  entrance  of  micro-organisms  harbored  in  the  accessory  cavi- 
ties .of  the  skull. 

2.  True  heat  stroke,  is  much  more  complex  in  nature  and  develop- 
ment* and  occurs  in  general  hyperthermy.  It  is  well  known  that 
man  can  adapt  himself  to  considerable  degrees  in  variations  of 
outside  temperature  by  virtue  of  a  nervous  regulatory  mechanism. 
If,  for  example,  the  outside  heat  rises,  the  skin  vessels  dilate, 
perspiration  and  respiration  become  more  active  and  thus  by 
increased  heat  dissipation  the  body  temperature  is  prevented 
from  rising.  For  this  reason,  man  can  exist  for  a  long  time  in  high 
and  dry  heat.  But  if  the  surrounding  air  is  not  only  hot,  but  moist, 


TEMPERATURE— HEAT  AND  COLD  139 

heat  dissipation  is  made  correspondingly  difficult.  Consequently, 
especially  during  activity,  the  body  heat  will  rise  and  hyperthermy 
follows  (39°  to  40°C). 

Hyperthermy  shows  itself  by  lassitude,  headache  and  oppressive 
sensations.  If  the  heat  influence  is  not  relieved  respiratory  dyspnea 
follows.  (The  dog  which  does  not  perspire  shows  polypnea  as 
the  method  of  heat  dissipation  much  sooner  than  man.)  Thus  the 
intake  of  O  and  the  output  of  CO2  rise,  nervous  manifestations 
become  pronounced  (vomiting,  anuria),  convulsions  occur  and 
death  results  from  paralysis  of  nervous  centers  from  hyperthermy. 
Just  before  death  the  body  temperature  rises  tremendously  (41° 
to  45°,  even  47°C.)  and  the  skin  is  dry  and  hot.  Autopsy  shows 
hyperemia  and  venous  congestion  of  the  nervous  system,  blood 
stasis  in  viscera  and  marked  rigor  mortis,  especially  of  the  heart. 

COLD.  The  results  of  outside  cold  depend,  like  those  of  heat, 
upon  the  degree,  length  of  action,  extent  and  the  medium.  As  a 
rule  the  vitality  of  tissues  is  less  susceptible  to  cold  than  to  heat. 
Cold  air  lowers  body  temperature  by  radiation,  but  not  so  energet- 
ically or  marked  as  wet  clothing  through  conduction.  Tissues  may 
be  preserved  in  cold,  because  it  excludes  bacterial  action  and  heat 
which  are  necessary  for  chemical  decomposition  and  autolysis. 
Such  tissues  may  be  later  revived  by  placing  them  under  suitable 
conditions  as,  for  example,  by  transplantation  into  animals  of  the 
same  species.  Thus  Ehrlich  succeeded  in  transplanting  a  cancer  of  a 
mouse  into  another  after  two  years  preservation  at  a  temperature 
of -8  to  -I2°C 

Rapid  freezing,  however,  is  followed  by  necrosis,  and  death  of 
tissues.  Cold-blooded  animals  like  frogs  and  fish  may  survive 
freezing  if  this  is  incomplete  and  thawing  is  carried  out  gradu- 
ally. This  gradual  restitution  to  normal  temperatures  is  impor- 
tant, as  rapid  rise  of  temperature  causes  hemolysis.  Even  in 
warm-blooded  animals  the  heart  has  been  frozen  and  then  revived. 

The  local  action  of  intense  cold  on  the  skin  is  somewhat  like 
that  of  heat,  except  that  the  hyperemia  is  preceded  by  anemia  of 
the  parts.  Inflammation  (frost-bite)  follows,  often,  as  in  heat  action, 
with  blister  formation  and,  unless  relieved,  gangrene  of  the  exposed 
tissues. 


1 40  GENERAL  PATHOLOGY 

In  depressed  individuals  (drunkards),  exposure  to  very  mild 
degrees  of  cold  is  often  sufficient  to  cause  serious  local  conse- 
quences, especially  when  the  cold  is  moist.  This  is  probably  due  to 
prolonged  arterial  spasm.  Adaptation  to  cold,  is,  in  healthy  indi- 
viduals, greater  than  for  heat.  Death  occurs  when  the  temperature 
of  the  whole  body  declines  below  2o°C.,  but  resuscitation  has  been 
possible  where  the  body  temperature  had  already  reached  26°C. 
or  even  24°C. 

The  general  effects  of  exposure  to  milder  degrees  of  cold  are 
usually  expressed  in  the  term,  "catching  cold,"  that  is,  catarrh, 
or  pains  in  joints  and  muscles.  Catching  cold  as  direct  influence 
of  the  cold  was  formerly  given  an  important  place  as  an  etiological 
factor  in  disease;  to-day  we  know  that  its  effect  is  mostly  indirect 
by  favoring  invasion  and  action  of  bacteria,  more  especially 
through  vascular  anemia  and  inhibition  of  cell  functions.  This 
effect  seems  much  more  marked  when  the  change  from  warm  to 
cold  is  rapid  and  in  great  contrast.  Mucous  membranes  and  lungs 
are  especially  susceptible  to  such  temperature  changes,  apparently 
through  a  variety  of  circumstances,  that  is,  cold  favors  the  secretion 
of  abundant,  thin,  non-protecting  mucus,  which  loosens  the 
surface  cells;  thus  bacteria  enter  and  penetrate  into  and  through 
anemic  parts  which  are  unable  to  exercise  their  normal  bactericidal 
faculties. 

The  general  predisposing  effects  of  cold  were  well  demonstrated 
by  Pasteur  in  exposing  hens  which  are  ordinarily  immune  to 
anthrax  to  cold  air.  They  were  made  susceptible.  The  same  is  true 
of  guinea  pigs  towards  pneumococcus  infections.  It  is  also  possible 
that  cold,  by  retarding  and  interfering  with  metabolic  proc- 
esses, leads  to  incomplete  oxidation  and  accumulation  of  waste 
products  in  tissues  and  thus  gives  rise  to  muscle  stiffness  and  pains 
(neuralgia). 


CHAPTER  XXIV 
AIR  PRESSURE 

AIR  pressure  affects  the  organism  either  by  diminution  or  in- 
crease. 

i.  The  actions  of  diminished  air  pressure  occur  in  high  alti- 
tudes or  artificially  in  the  pneumatic  cabinet.  Its  effect  is  usually 
complicated  by  the  additional  influences  of  the  sun,  air,  electrical 
conditions,  etc.  The  most  characteristic  effect  is  on  the  blood.  It 
has  been  known  for  some  time  that  the  blood  of  man  and  animals  in 
high  altitudes  possesses  increased  ability  for  O  absorption,  and  this 
is  later  associated  with  actual  increase  in  red  blood  cells  (poly- 
cythemia).  This  is  due  to  diminution  of  partial  O  pressure,  for  it 
does  not  occur  in  the  pneumatic  cabinet  with  full  O  pressure.  The 
number  of  red  blood  cells  rises  to  about  8  millions  in  a  cubic  milli- 
meter. On  return  to  low  altitude  it  declines  to  normal. 

The  cause  of  the  red  blood-cell  increase  is  primarily  possibly 
due  to  thickening  of  the  blood  as  the  result  of  water  output  through 
increased  respiration  in  order  to  adapt  the  organism  to  the  lessened 
O  tension.  But  later  there  is  also  increased  transportation  of  cells 
from  the  bone  marrow  into  the  circulation.  Subjective  character- 
istic manifestations  appear.  The  pulse  becomes  more  frequent  even 
in  moderate  altitudes  of  400  to  500  meters  (lessened  O  tension). 
This  increased  rate  may  be  diminished  by  O  inhalation.  The  same 
is  true  of  increased  respiration,  which  depends  upon  lessened  O 
tension  in  the  alveolar  air.  Presence  of  the  air  in  the  tympanic 
cavity  against  the  drum  causes  ringing  in  the  ear.  Gradually  these 
symptoms  increase  to  what  is  known  as  mountain  sickness.  The 
individual  predisposition  to  this  varies.  Some  do  not  suffer  from  it 
at  all;  in  others  an  altitude  of  from  3000  to  5000  meters  is  sufficient. 
In  severe  cases,  hemorrhages  from  nose,  mouth  and  ears,  air 
hunger,  nervous  symptoms  and  even  death  follow, 

141 


i42  GENERAL  PATHOLOGY 

The  symptoms  of  mountain  sickness  can  only  partly  be  explained 
by  lack  of  O.  Mechanical  differences  in  the  circulatory  pressure 
between  lungs  and  body  surface  probably  add  to  the  difficulty. 
Rupture  of  the  lung  may  occur.  Rabbits  die  in  rapid  air  dilution 
with  6  per  cent.  O  in  the  air  in  about  one  hour;  but  with  sufficient 
air  pressure  may  live  even  with  4.7  per  cent.  O. 

Disease  resulting  from  increased  air  pressure  is  most  frequent  in 
persons  working  in  compressed  air,  such  as  divers,  tunnel  workers, 
and  others  who  labor  in  caissons.  The  effects  do  not  depend  so  much 
upon  the  pressure  increase  as  upon  the  rapidity  with  which  com- 
pression and  especially  decompression  are  accomplished.  The  blood 
is  unchanged.  The  pulse  is  lowered  in  i  to  3  atmospheres  about  15 
beats.  Ear  symptoms  are  marked;  sensation  of  pressure  on  the 
drum,  hemorrhages  from  the  ear  and  rupture  of  the  tympanum. 
This  danger  exists  when  the  pressure  rises  over  o.i  atmosphere  in 
1%  minutes.  Whistling  and  whispering  become  impossible  in  three 
atmospheres.  The  longer  and  stronger  the  compression,  the  greater 
the  N  contents  of  the  blood.  Sudden  decompression  has  liberated  as 
much  as  1700  c.c.  N.  This  sudden  volume  of  N  evolves  gas  bubbles 
in  the  blood  and  leads  to  dangerous  gas  emboli. 

Clinically  caisson  disease  is  characterized  by  muscle  and  joint 
pains,  paresis  and  even  paraplegia  of  legs,  ear  vertigo  and  convul- 
sions. These  symptoms  are  largely  due  to  the  occurrence  of  gas 
(N)  emboli  in  blood  vessels  of  the  spinal  cord,  followed  by  softening 
of  the  cord  structure.  Heart  paralysis  in  these  cases  results  from 
gas  in  the  heart's  blood.  To  prevent  caisson  disease,  gradual  decom- 
pression is  absolutely  necessary,  at  least  two  minutes  for  o.i  at- 
mosphere. A  workingman  in  20  meters  depth  should  be  decom- 
pressed for  40  minutes  with  massage  and  occasional  recompression, 
if  required.  Debilitated  or  weakened  subjects  or  workingmen  after 
alcoholic  debauch  should  be  rejected  altogether  for  caisson  work. 


CHAPTER  XXV 
ELECTRICITY— X-RAYS— RADIUM 

ELECTRICITY.  Resting  electricity  produces  no  reaction  in  the 
animal  organism.  But  active  electrons  or  electrically  charged 
atoms  are  of  great  biological  and  pathological  importance.  It  is 
necessary  to  distinguish  between,  (i)  the  effects  of  electric  discharge 
from  a  condenser  (fulguration),  and  (2)  the  effect  of  an  electric 
current. 

i.  Rapid  discharge  from  a  condenser  is  best  exemplified  in 
lightning.  Men  and  animals  struck  by  lightning  show  evidences 
of  it  on  the  surface  of  their  bodies  in  the  majority  of  cases.  These 
consist  in  punctate  or  streaky  hemorrhages,  burns  and  singeing  of 
hairy  parts.  The  burnt  areas  display  generally  a  characteristic 
shining,  pearly  appearance  as  the  result  of  electrolytic  processes, 
and  these  may  appear  on  a  protected  skin. 

But  deeper  penetration,  destruction,  tearing  of  the  skin  and 
actual  holes  may  occur.  Very  peculiar  are  red  zig-zag,  arborescent 
figures  on  the  surface  of  the  skin,  known  as  "Lichtenberg  figures. " 
These  are  painful,  disappear  and  are  not  burns,  but  vasomotor 
phenomena.  Veins  are  usually  prominent,  engorged.  Turbidity  of 
the  lens  and  cataracts  occur  also  in  a  number  of  cases  from  electro- 
lytic changes  in  the  eye.  Death  takes  place  in  about  40  per  cent,  of 
individuals  struck  by  lightning.  Much  depends  upon  the  part  of  the 
body  which  is  struck;  thus,  lightning  on  the  head  is  always  fatal, 
on  the  extremities  never.  In  all  cases  loss  of  consciousness  occurs, 
at  least  momentarily,  and  sometimes  extending  to  hours,  then  motor 
or  sensory  paralysis.  Severe  cases  have  convulsions  and  coma.  The 
pulse  is  first  small  and  slow,  then  becomes  full  and  frequent; 
respiration  is  stertorous;  diarrhea  and  albuminuria  are  frequent. 
Autopsy  shows  rapid  rigor  mortis,  marked  general  acute  blood 
congestion  and  hemorrhages,  especially  of  the  central  nervous 

143 


144  GENERAL  PATHOLOGY 

system.  Death  seems  to  ensue  from  respiratory  paralysis.  It  is 
reported  that  artificial  respiration  may  still  save  life. 

2.  The  action  of  electric  currents  has  been  well  recognized  in 
physiological  experiments  in  the  results  of  the  intermittent  and 
constant  currents.  These  need  not  be  considered  here.  Long  action 
of  both  leads  to  degeneration  and  disintegration  of  nervous 
structures. 

The  effects  of  high  currents  have  acquired  importance  in  modern 
industries  and  in  electrocutions.  The  resistance  of  the  human  body 
has  been  calculated  at  about  747  ohms.1  Death  from  intermittent 
currents  is  due  to  paralysis  of  heart  and  nerve  centers.  Experiments 
on  dogs  have  shown  that  an  intermittent  current  of  120  volts, 
applied  between  head  and  legs,  kills  through  respiratory  central 
paralysis,  while  the  heart  continues  to  beat.  Electric  currents  of 
not  over  120  volts  in  the  direction  from  head  to  feet  cause  death 
from  heart  paralysis  while  the  respiration  continues.  High-tension 
currents,  even  up  to  4800  volts,  may  not  kill  an  animal  instan- 
taneously (over  a  second)  if  artificial  respiration  is  carried  out  as 
the  heart  is  not  paralyzed.  At  autopsy  is  found  hyperemia  of 
organs, fluid  blood  (from  asphyxia)  and,  in  heart  death,  early  rigor 
mortis.  The  skin  shows  burns  in  longer  contact. 

The  action  of  constant  currents  is  very  similar  to  those  of  the 
intermittent,  but  the  heart  and  nervous  system  are  not  affected  as 
easily  as  in  intermittent  currents  (to  150  volts).  In  electrocutions 
1500  to  2000  volts  were  originally  applied  for  several  seconds.  In 
these  cases  occurred  rise  in  temperature,  fumes  at  the  electrode 
sponges  and  reappearance  of  heart  and  respiratory  movements.  To 
prevent  this,  intermittent  applications  of  high  and  low  tension  were 
instituted,  that  is,  1500  to  1700  volts  for  5  to  7  seconds  and  200  to 
400  volts  for  30  seconds.  This  is  repeated  as  long  as  the  delinquent 
breathes.  The  effect  is  immediate  loss  of  consciousness,  tetanic 
contractions  of  muscles  and  heart  paralysis  from  the  lower  tension 
currents.  At  immediate  autopsy  fibrillar  muscle  action  may  still 
be  visible  in  the  heart,  but  is  followed  rapidly  by  rigor  mortis. 

Volts 
1  Ohm  =  Am      e»  is  unit  expression  of  resistance.  Volt  =  electrical  unit, 

that  is,  the  electromotive  force  in  a  conductor  whose  resistance  is  one  ohm 
and  which  produces  a  current  of  one  ampere. 


ELECTRICITY— X-RAYS— RADIUM  145 

In  electric  industries  contact  with  electrically  charged  wires  may 
have  several  consequences — burns,  pains,  temporary  loss  of  con- 
sciousness, and  death.  Burns  are  the  result  of  heat  production  at 
the  points  of  the  electrodes  and  may  be  deep,  leading  to  circum- 
scribed defects  in  the  skin.  These  burns  increase  the  resistance 
of  the  skin.  Pain  follows  the  strong  tonic  muscular  contractions. 
Loss  of  consciousness  occurs  immediately  on  bringing  the  current 
in  contact  with  the  head  or  even  limbs.  This  coma  lasts  several 
minutes.  Convulsions  do  not  occur.  Intermittent  currents  of 
1 20  volts  (used  for  feeding  arc  lights)  cause  death,  but  usually 
much  higher  intermittent  currents  (4000  to  5000)  and  constant 
currents  of  1500  volts  are  involved.  High-tension  currents  (inter- 
mittent currents  of  2000  volts)  are  usually  not  fatal  unless  the 
electromotive  force  is  diminished  by  the  resistance  of  the  body, 
when  heart  paralysis  occurs.  While  burning  of  the  skin  increases 
resistance,  moist  skin  lessens  it.  Currents  through  a  leg  (boot)  and 
hand  are  less  dangerous  than  through  both  hands,  therefore  some 
shops  warn  workingmen  to  always  put  one  hand  in  a  pocket.  In 
death  the  injured  individual  may  utter  a  cry,  fall  to  the  ground 
from  heart  paralysis  and  with  a  general  tetanic  contraction  of  the 
body.  Artificial  respiration  is  here  useless. 

X-RAYS  AND  RADIUM.  The  action  of  x-rays  and  radium  may 
be  shortly  summarized.  Roentgen  rays  and  gamma  rays  of  radium 
are  of  very  short  wave  lengths.  It  appears  that  the  effect  of  these 
rays  is  due  to  negatively  charged  ions  which  they  set  free  by  pas- 
sage through  atoms.  In  small  doses  these  are  stimulating;  in  large 
doses  destructive  to  cells,  especially  to  the  nucleus. 

Hertwig  has  performed  interesting  experiments  on  frogs,  by 
which  he  showed  that  the  nucleus  of  a  sex  cell  may  be  so  damaged 
by  exposure  to  radium  that  it  is  unable  to  enter  into  relation  with 
the  untreated  nucleus  of  the  opposite  sex,  although  it  may  still 
possess  the  power  to  initiate  maturation  division  of  the  ovum  or, 
if  untreated,  to  cause  division  of  the  treated  egg  and  furnish  a  male 
nucleus.  Practically  it  has  been  recognized  for  a  long  time  that 
long-continued  exposure  to  x-rays  induces  sterility. 

The  local  effects  on  tissues,  which  have  been  especially  studied 

in  the  skin,  are  destructive  lesions  in  fixed  cells  (pyknosisof  nucleus 
10 


146  GENERAL  PATHOLOGY 

and  cell  lysis) ;  changes  in  the  vessels  and  connective  tissue  sclero- 
sis. Milder  lesions  are  much  like  burns;  when  these  become  exces- 
sive they  exhibit  little  tendency  to  heal.  Surface  granulation  tissue 
remains  imperfect  and  on  the  skin  epidermization  does  not  take 
place,  or  is  very  poor.  Deeper  tissues  exhibit  a  marked  hyaline 
sclerosis,  making  up  an  almost  homogeneous  non-nucleated  layer. 
The  blood  vessels  exhibit  extraordinary  intimal,  fibrous  thickening 
leading  either  to  obliteration  or  narrowing  of  the  lumen.  From 
such  unstable,  pathological  scars  cancers  not  infrequently  develop, 
probably  from  degenerated,  misplaced  epidermal  cells. 

Effects  on  tumor  cells  and  tissues  are  similar  to  those  of  normal 
tissue  or  upon  inflammatory  tissue.  Lymphoid  and  myeloid  (bone 
marrow)  cells  are  normally,  and  in  tumors  apparently  somewhat 
more  susceptible,  to  the  destructive  effects  than  other  cells.  It  is 
possible  that  beneficial  effects  observed  by  #-ray  or  radium  treat- 
ment in  lymphosarcomata  and  leukemia  may  be  due  to  this  greater 
sensitiveness.  Generally  speaking,  however,  the  use  of  these  rays 
in  treatment  of  actively  growing  tumors  is  not  followed  by  very 
encouraging  results. 


CHAPTER  XXVI 

POISONS  (TOXICOLOGY) 

SUBSTANCES  which  cause  disease  by  their  chemical  nature  and 
through  toxic  action  are  poisons,  and  their  detailed  study  belongs 
to  the  domain  of  toxicology.  In  general,  however,  their  action,  like 
that  of  any  chemical  reagent,  depends  upon  chemical  reactions 
into  which  they  enter  with  the  components  of  cell  protoplasm. 
Their  toxic  action,  therefore,  depends  upon  their  affinity  for  cer- 
tain cell  constitutents  and  this,  in  turn,  is  due  to  their  chemical 
constitution.  Thus  all  chemical  poisons  act  as  (i)  irritants,  (2) 
blood  poisons,  (3)  nervous  poisons,  (4)  heart  and  vascular  poisons, 
(5)  parenchymatous  poisons  (on  essential  organ  cells),  especially 
liver  and  kidney,  or  (6)  metabolic  poisons  (those  interfering  with 
metabolism;  for  example,  phosphorus). 


147 


PART  II 
THE  INTERNAL  FACTORS 


CHAPTER  XXVII 
DISPOSITION  AND  IDIOSYNCRASY 

INTERNAL  factors  of  disease  are  those  which  are  inherent,  or  take 
origin,  in  the  organism  itself.  Their  nature  is  less  clear  and,  neces- 
sarily, much  more  difficult  for  analysis  than  of  that  the  external 
causes.  The  reason  lies  partly  in  the  complexity  of  the  animal  body 
and  partly  in  our  ignorance  of  the  exact  methods  by  which  the 
various  energies  of  the  outside  world  enter  into  relation  with  the 
body.  This  ignorance  makes  an  understanding  of  the  part  or  parts 
which  the  organism  plays  in  this  interchange  difficult  and  often 
hazy.  We  are  able  to  distinguish,  however,  between  two  main  in- 
ternal factors  which  determine  the  general  attitude  of  the  organ- 
ism towards  the  external  causes  of  disease.  These  are  (i)  disposition 
and  idiosyncrasy,  (2)  heredity. 

The  word  disposition  or  predisposition  is  derived  from  the  Latin 
disponere,  to  get  ready.  It  means  that  an  organism  is  in  parts,  or 
as  a  whole,  particularly  exposed  or  leans  towards  certain  outside 
influences.  The  disposed  state  remains  latent  until  the  correlated 
external  influence  meets  it. 

Disposition  may  be  either  congenital  or  acquired.  The  congenital, 
again,  may  be  hereditary  in  the  true  sense  of  the  term,  or  acquired 
in  utero.  Hereditary  dispositions  are  germinative,  that  is,  due  to 
conditions  of  the  germ  plasm.  All  others,  whether  acquired  in  or 
outside  of  the  uterus,  are  developmental.  Disposition  to  disease 
may  be  either  general  (non-specific),  or  individual  (specific).  The 
general,  non-specific  dispositions  depend  upon  lowered  or  reduced 
cell  activities  which  result  from  such  general  influences  as  hunger, 
cold,  fatigue,  malnutrition.  These  are,  as  we  have  had  already 
occasion  to  note,  predisposing  agents,  which  through  a  number  of 
factors  make  the  body  more  susceptible  and  receptive  to  outside 
influences.  They  endanger,  or  even  destroy,  by  interference  with 
body  functions,  that  balance  or  ensemble  of  tissues  by  which  the 

151 


1 52  GENERAL  PATHOLOGY 

organism  maintains  its  relative  equilibrium  against,  and  indepen- 
dence from,  the  outside  world. 

On  the  other  hand,  individual  specific  dispositions  depend  upon 
definite  congenital  or  developmental  structural  physical  characters 
and  tendencies.  These  may  be  latent  or  active.  A  latent  disposition 
may  be  translated  into  an  active  one  by  developmental  processes ; 
for  example,  by  growth,  by  puberty,  by  pregnancy  and  old  age.  The 
disposition  becomes  then  specific.  These  specific  dispositions  are 
referred  to  as  constitutions  or  diatheses.  Thus,  one  speaks  of  an 
anemic  or  apoplectic  constitution,  and  means  types  of  individuals 
in  which  certain  outside  influences  lead  more  readily  to  anemia  or 
apoplexy  than  in  others.  Some  of  these  types  depend  upon  very 
easily  demonstrable  anatomic  peculiarities ;  for  example,  an  under- 
development  of  heart,  arteries  or  other  organs. 

Anatomical  peculiarities  may  thus  effect  whole  trees  of  families 
and  generically  predispose  them  to  certain  diseases  more  than 
others.  Besides  these  anatomical  dispositions,  attention  has  lately 
been  directed  to  certain  functional  cell  relations  which  enter  into 
the  production  of  disease.  We  have  seen  that  the  body  of  metazoa 
consists  not  only  of  collections  of  cells,  but  is  differentiated  into 
cell  territories  or  organs.  All  these  stand  in  biological  relation  to 
each  other  and  this  relation  is,  even  under  normal  conditions,  not 
always  altruistic,  but  sometimes  antagonistic. 

These  influences  are  especially  well  exemplified  in  the  growing 
organism,  more  particularly  in  the  embryo.  Here  we  meet  practi- 
cally all  pathological  tissue  and  organ  changes  as  normal  and 
coordinated  physiological  phenomena  of  evolution.  "Without  ne- 
crobiosis  and  degeneration  on  a  large  scale,"  Minot  once  remarked, 
"the  normal  round  of  human  life  would  be  impossible."  Thus,  the 
early  death  of  the  polar  bodies,  the  degeneration  of  the  mesone- 
phros  which  is  due  to  the  development  of  the  sex  gland,  the  disap- 
pearance of  the  notochord  and  other  embryonic  tissues,  the  necrosis 
and  resorption  of  the  decidua  reflexa,  etc.,  are  dependent  upon 
growth  and  antagonism  of  other  organs.  Such  interferences  con- 
tinue in  post-natal  life  as  shown  by  the  gradual  disappearance 
of  the  thymus,  lymphoid  tissues,  sloughing  of  the  menstrual  uterine 
mucosa,  etc.,  and  they  are  evident  in  the  constant  neutralizing  or 


DISPOSITION  AND  IDIOSYNCRASY  153 

antagonistic  actions  of  certain  organs  of  internal  secretion  (thyroid 
against  pancreas  and  pancreas  against  suprarenal  gland)  (see 
later  under  Disturbance  of  Internal  Secretion). 

Just  how  far  these  internal  actions  are  responsible  for  specific 
diseases  and  how  much  they  may  predispose  the  body  generally  at 
one  time  or  another  of  human  existence  to  harmful  outside  influ- 
ences is  still  uncertain.  But  that  their  influence  is  potent  can  no 
longer  be  doubted. 

Thus  it  follows  that  in  any  classification  of  disposition,  the  dis- 
position of  age  is  of  great  importance,  for  the  physical  organization 
of  age  periods  varies;  with  the  introduction  of  new  factors,  others 
are  eliminated.  Consequently,  body  relations  to  outside  stimuli 
vary  in  different  age  periods. 

The  disposition  of  age  is  caused  by  growth  and  regression  of  the 
organism.  Man  at  no  time  of  his  existence  is  in  perfect  equilibrium; 
within  him  are  constantly  proceeding  evolutionary  changes  which 
consist  of  regression  and  progression  in,  and  annihilation  and 
reformation  of,  cells,  tissues,  organs.  Thus  the  physical  organization 
differs  in  the  great  age  periods  of  human  existence.  But  even  within 
these  periods  organs  are  never  absolutely  fixed  in  cell  type  and 
organization,  but  constantly  involute  and  evolute.  This  fluid  con- 
dition of  tissues  and  organs  makes  possible  interaction  with  the 
outside  world,  but  also  creates  the  danger  of  upset  of  balance  in 
retrogression  and  progression  beyond  the  physiological  sphere,  and 
the  inauguration  of  pathological  life.  We  can  recognize,  as  life 
changes  from  infancy  to  old  age,  definite  greater  periodic  advances; 
and,  within  these  periods,  individual,  evolutionary  changes. 

Thus,  six  great  periods  of  life  have  been  long  distinguished: 

1.  Infancy;  the  period  of  extrauterine  dependency  upon  the 
mother  (7  to  10  months,  to  time  of  independent  nutrition  and 
motion). 

2.  Childhood;  to  second  teething  (7  years)  comprises  inde- 
pendent motion,  speech  and  development  of  senses. 

3.  Presexual  age;  to  beginning  of  puberty  (13  to  16  years). 

4.  Puberty;  to  end  of  length  growth  (20  to  25  years), 

5.  Maturity;  full,  individual  development  to  sexual  cessation 
(about  45  years  in  women,  uncertain  in  men). 

6.  Senility,  period  of  external  decline  to  death. 


154  GENERAL  PATHOLOGY 

In  each  of  these  periods  the  organization  of  the  body  possesses 
physical  characteristics  of  its  own  and  thus  determines  the  dis- 
position by  removing  certain  structures  and  introducing  others. 
Naturally,  also,  manifestations  and  expressions  of  a  disease  stand 
under  the  influence  of  age  organization.  Thus,  for  example,  children 
and  youths  in  whom  the  lymphoid  system  is  highly  developed  and 
active,  display  a  tendency  towards  infections  and  diseases  of 
lymphoid  tissues  (tuberculosis,  etc.);  or,  on  account  of  the  un- 
stable and  growing  character  of  bones,  to  certain  bone  diseases 
such  as  rickets,  osteomyelitis,  etc.  Again,  infantile  diarrheas  occur 
most  frequently  at  the  time  of  beginning  independence  from  the 
mother,  when  the  gastro-intestinal  tract  must  adapt  itself  to 
new  environment.  Furthermore,  the  whole  period  and  diseases 
of  puberty  stand  largely  under  the  ban  of  sexual  development 
(chlorosis,  nervous  diseases).  When  later  sexual  organs  become 
useless  and  atrophic  and  other  involutionary  changes  occur,  the 
ground  is  prepared  for  cancer,  arteriosclerosis  and  degenerative 
lesions. 

The  finer  evolutionary  changes  in  individual  organs  within  these 
great  and  general  age  periods  are  difficult  of  analysis  and  classifica- 
tion. They  are  deeply  seated,  variable  in  expression  in  different 
organs  and,  therefore,  not  as  easily  recognized  and  classified  as  the 
plainer  external  attributes  of  age.  But  we  know  that  in  some  organs, 
like  those  of  internal  secretion,  the  bone  marrow,  the  spleen, 
lymphoid  tissue  generally,  the  pancreas  and  the  sex  glands,  tissues 
are  very  fluid,  never  absolutely  fixed,  but  constantly  in  cell  re- 
gression and  progression.  So  that  throughout  life  these  organs  are, 
even  within  a  given  age  period,  unstable  in  their  structures.  It  is 
difficult  to  lay  down  for  them,  at  any  time,  any  fixed  normal 
standards. 

Somewhat  more  easily  recognized  are  general  organ  changes 
which  correspond  to  great  age  periods.  Thus  in  the  spleen,  for 
example,  Gross  showed  that  young  spleens  differ  in  essentially  all 
components  and  structure  from  adult  and  senile  spleens,  and  that 
the  reactions  of  the  spleen  to  disease  are  accordingly  modified  by 
the  age  period.  He  has  expressed  these  changes  in  curves  which 
are  here  reproduced. 


DISPOSITION  AND  IDIOSYNCRASY 


155 


In  the  following  charts  "subgroups"  refer  to  age  periods:  a 
represents  the  first  five  years,  b,  etc.,  decades. 


FIG.  i. — It  will  be  seen  that  the  inci- 
dence of  small  spleens  from  being  eight 
per  cent,  in  the  first  five  years  of  life  is 
represented  as  eighty  per  cent  between 
the  ages  of  seventy-six  to  ninety.  This 
is  a  convenient,  graphic  way  of  expressing 
the  fact  that  the  spleen  undergoes  a 
gradual  atrophy.  That  the  smallness  is 
not  only  due  to  atrophy,  but  also  to  some 
other  factor,  viz.,  collapse,  will^be  shown 
by  Figs.  9.  10,  and  12. 


FIG.  3. — A  curious  finding  is  the 
occurrence  diffusely  as  well  as  in  groups 
of  small,  round  cells  in  the  capsule. 
Very  infrequent  early  in  life,  it  is  seen  in 
ninety  per  cent  of  capsules  in  Subgroup 
"I."  The  infiltration  may  not  be  very 
extensive,  but  it  is  definitely  noticeable. 


FIG.  2. — Shows  that  there  is  a  gradual 
rise  in  the  incidence  of  soft  spleens  until 
thirty-six  to  forty-five  years.  From  this 
there  is  ju  sudd  en  drop.  It  appears  from 
this  that  the-  spleen  reacts  most  vigorously 
to  disease  during  middle  Iif0.  (The  soft 
spleens  under  consideration  are  the  mushy 
friable  variety  usually  seen  in  acute  inflam- 
mation.) 


FIG.  4. — The  capsule  shows  a  gradual 
and  progressive  thickening.  From  the 
age  of  thirty  on,  practically  every 
capsule  shows  a  considerable  hyaline 
change  of  its  connective  tissue,  the  nuclei 
of  the  fibroblasts  largely  disappear  and 
the  fibrils  become  thickened  and  fused. 


i56 


GENERAL  PATHOLOGY 


PIG.  5. — The  spleen  at  birth  presents 
numerous,  tiny  capillaries  as  well  as 
endothelial  buds.  It  appears  from  this 
that  the  vasculature  of  the  spleen  is  not 
complete  at  birth.  Fig.  5  shows  how 
rapidly  the  incidence  of  these  endothelial 
buds  declines.  Prom  ninety-three  per 
cent,  in  Subgroup  A,  it  falls  to^forty  per 
cent,  in  Subgroup  B. 


FIG.  6. — The  blood  vessels  undergo  a 
gradual  thickening.  This  thickening  is 
largely  intimal  and  medial,  and  consists 
of  a  connective  tissue  production  as  well 
as  of  a  hyaline  tissue  fusion. 


FIG.  7. — It  is  remarkable  how  early 
in  life  the  splenic  blood  vessels  undergo  this 
hyaline  change.  From  the  thirty-sixth 
year  on,  practically  every  spleen  shows 
this  phenomenon.  The  hyaline  transforma- 
tion commences  in  the  intima  and  later 
involves  and  replaces  the  media. 


FIG.  8. — The  Malpighian  corpuscle 
consists  at  birth  of  a  tiny  arteriole  sur- 
rounded eccentrically  by  a  rather  compact 
lymphoid  mantle.  This  mantle  is  per- 
meated by  capillaries  which  are  invisible 
in  very  young  spleens.  Very  soon, 
however,  they  become  thickened,  promi- 
nent and  later  hyaline,  so  that  at  thirty- 
six  years  practically  fifty  per  cent,  of 
spleens  show,  instead  of  one  arteriole,  a 
number  of  more  or  less  thickened  and 
tortuous  vessels  coursing  through  each 
Malpighian  corpuscle. 


DISPOSITION  AND  IDIOSYNCRASY 


157 


Pi1 


FIG.  9. — The  trabeculae  of  the  spleen 
do  not  present  a  very  marked  thickening 
until  about  the  fiftieth  year,  when  there  is 
an  abrupt  increase  in  amount,  which 
rapidly  progresses.  This  appearance,  as 
will  later  be  seen,  is  in  part  due  to  collapse 
of  splenic  pulp  which  renders  the  trabeculae 
relatively  more  prominent.  There  is,  how- 
ever, as  a  matter  of  fact,  an  actual 
fibrous  tissue  thickening  of  the  trabeculae. 


PIG.  10. — The  amount  of  lymphoid 
tissue  as  estimated  by  the  size  and  number 
of  Malpighian  corpuscles  falls  steadily 
from  birth.  The  collapse  of  the  splenic 
pulp  in  later  life  tends  to  obscure  this  fact 
somewhat  in  bringing  these  bodies  closer 
together  and  thus  presenting  a  relatively 
larger  quantity  per  volume  of  spleen. 
There  is,  however,  undoubtedly  a  decrease 
in  the  actual  amount  of  lymphoid  tissue 
with  progressing  age. 


FIG.  n. — In  the  first  five  years  of  life 
about  forty-three  per  cent,  of  spleens 
present  active  germinal  centers  in  their 
lymphoid  follicles.  This,  however,  very 
quickly  disappears. 


FIG.  12. — Lastly,  the  spleen  shows  a 
gradual  increase  in  amount  of  pulp  with 
increasing  years.  This  is  probably  largely 
due  to  the  gradual  collapse  of  the  tissue. 


158  GENERAL  PATHOLOGY 

Thus,  in  early  life  the  spleen  is  a  very  vascular,  lymphoid  and 
actively  growing  structure.  During  this  period  its  reactions  to  dis- 
ease are  not  marked  but  its  relations  to  the  blood  are  very  intimate. 
With  progressive  age,  lymphoid  tissue  falls,  the  pulp  collapses, 
blood  vessels,  reticulum  and  trabeculse  thicken,  and  the  spleen 
reacts  more  strongly  to  outside  influence.  In  old  age  all  its  struc- 
tures have  undergone  such  regression  that  its  participation  in 
disease  is  very  sluggish  and  uncertain. 

Far-reaching  architectural  changes  may  also  be  demonstrated 
for  different  age  periods  in  the  heart,  especially  in  its  circulatory 
arrangement.1  Here  it  is  even  possible  to  recognize  an  age  period  by 
the  qualitative  as  well  as  quantitative  vascular  construction,  by 
blood  supply  to  the  right  and  life  side  and  by  the  musculature.  In 
other  organs,  like  the  liver  and  kidney  and  especially  in  still  lower, 
more  vegetative  tissues,  regressive  and  progressive  changes  pro- 
ceed, under  normal  conditions,  more  slowly,  and  are  more  limited, 
so  that  these  tissues  maintain  throughout  a  more  permanent 
anatomical  arrangement  and  cell  type.  The  importance  of  this 
fluid,  ever-changing  condition  of  body  structures  is  obvious,  for, 
if  the  physiological  balance  of  regression  and  progression  is  dis- 
turbed, pathological  exaggerations  of  one  or  the  other  result. 
Moreover,  such  organs  are  more  vulnerable  to  an  attack  during 
certain  periods  of  evolution  than  during  others. 

In  sexual  disposition  we  can  distinguish  two  classes,  the  first 
depending  upon  male  and  female  characters,  the  second  depending 
upon  the  differences  of  the  age  periods.  It  may  be  stated  as  a 
general  proposition  that  women,  by  virtue  of  their  extensive  sex 
organization,  stand  more  under  sexual  influences  than  man. 

Race  disposition  is  also  important.  Different  animals  show,  as  we 
already  know,  very  different  susceptibilities  towards  external 
causes  of  disease.  In  the  human  race  the  negro  is  more  tolerant  to 
heat  than  the  white  man,  but  less  to  infectious  diseases.  Even  in 
one  and  the  same  race  the  individual  biological  differences  (see 
later  under  Transplantation)  confer  variable  dispositions  towards 
outside  influences.  Finally,  there  exists  an  organ  disposition  de- 
pendent upon  the  cell  type  and  anatomical  arrangement  of  the 

JSee  Gross:  The  Blood  Supply  to  the  Heart.  Paul  B.  Hoeber,  New  York,  1921 . 


DISPOSITION  AND  IDIOSYNCRASY  159 

parts.  Kidney  and  spleen  are  by  virtue  of  their  anatomical  arrange- 
ment mechanically  more  exposed  to  retention  of  foreign  matter. 
But  besides  this  coarser  disposition  there  exist  as  yet  obscure 
tissue  affinities;  the  lung  for  tuberculosis  and  pneumonococcus 
infections,  the  gut  for  typhoid  infections,  etc. 

IDIOSYNCRASY.  Closely  related  to  disposition  is  idiosyncrasy. 
This  is  abnormal  exaggerated  individual  susceptibility  to  otherwise 
normal,  harmless  influences.  To  this  category  belongs  the  inability 
to  eat  certain  food  such  as  shellfish,  strawberries,  etc.,  without 
annoying  consequences.  Based  on  the  similarity  of  the  symptoms, 
idiosyncrasy  is  held  to  be  a  phase  of  anaphylaxis. 

The  ultimate  solution  of  disposition  rests  in  an  understanding  of 
those  conditions  under  and  through  which  an  organism  develops. 
A  knowledge  of  the  fundamental  principles  of  heredity  is,  there- 
fore, indispensable  to  the  physician,  especially  as  genetics  and 
eugenics  have  recently  been  brought  to  practical  tests  and  applica- 
tion for  legislative  action. 


CHAPTER  XXVIII 
HEREDITY 

THERE  is  hardly  any  other  field  of  science  which  has  been  more 
abused  and  crowded  with  unscientific  observations  and  conclusions 
than  heredity.  This  has,  in  a  certain  measure,  been  due  to  an  unusual 
popular  interest  and  a  remarkable  desire  on  the  part  of  some  public- 
spirited,  but  ignorant,  uncritical  persons  to  improve  the  human  race 
by  eugenic  (from  eu  =  well,  and  ytvvav  =  to  generate)  marriages  and 
eradication  of  evil  by  castration  of  undesirables. 

Apart  from  these  childish  abuses,  the  study  and  knowledge 
of  heredity  remain  of  greatest  value  and  importance,  for 
heredity  holds  the  key  to  the  understanding  of  the  disposition  to 
and  the  manifestations  of  disease.  Now  in  order  to  approach  the 
subject  properly  it  must  first  be  asked,  what  is  to  be  understood 
by  heredity? 

Heredity  is  organic  constitution  based  on  descent.  Excluded  from 
it  are  all  those  conditions  which  an  embryo  or  fetus  acquires  in  utero. 
These  give  rise  to  congenital,  but  not  hereditary  characters.  It 
is  an  error  to  use,  as  is  still  sometimes  done,  the  terms  hereditary 
and  congenital  synonymously.  Many  congenital  conditions  are 
individually  acquired,  only  before  individual  extrauterine  inde- 
pendence has  been  reached. 

Thus,  tuberculosis  and  syphilis,  sometimes  referred  to  as  heredi- 
tary diseases,  are  in  reality  infections  conveyed  directly  from 
mother  to  child  in  utero  (placental  infections).  Diseases  are 
processes  and  as  such  never  hereditary.  Hereditary  are  only  phys- 
ical qualities  (unit  characters)  which  an  environment  shapes  into  a 
definite  organic  expression.  These  qualities  reside  in,  and  are  trans- 
mitted by,  certain  definite  morphological  carriers  in  the  nuclei  of 
sex  cells  (chromosomes).  Parents  can,  therefore,  influence  their 

160 


HEREDITY  161 

offspring  in  no  other  way  than  through  a  change  in,  or  an  injury 
to  the  germ  plasma.  These  may  create  an  abnormal  or  faulty 
constitution  or  a  definite  disposition  to  a  disease  in  the  offspring, 
but  the  diseases  themselves  are  always  acquired,  either  in  utero, 
or  after  birth.  For  these  reasons  the  condition  of  the  mother  is, 
in  mammals  at  least,  of  paramount  importance  to  the  child,  for 
the  mother,  by  carrying  it,  nourishing  it  through  the  placenta, 
shapes  its  whole  somatic  development.  This  intrauterine  environ- 
ment is  for  mammals  of  greater  molding  importance  for  the  in- 
dividual than  extrauterine  life. 

Thus  only  qualities  are  hereditary;  moreover,  only  qualities  which 
exist  in  the  germ  substances  of  spermatozoon  and  ovum.  In  other 
words,  every  individual  possesses  certain  qualities  which  are  generic 
and  not  his  own,  and  certain  characteristics  which  are  individual 
and  his  own.  The  first  are  contained  in  his  sex  cells,  the  second 
depend  upon  the  environmental  influences  on  his  somatic  or  body 
cells. 

Now  the  great,  much-discussed,  question  has  been,  how  far 
environmental  influences  on  somatic  cells  may  influence  the 
relatively  isolated  sex  cells.  To  put  it  simply:  Can  acquired  in- 
dividual characters  be  handed  to  the  offspring? 

There  can  be  no  doubt  that  variability  is  a  property  of  living 
matter,  else  no  evolution  would  have  been  possible,  and  any  change 
which  occurs  during  the  process  of  evolution  may  be,  therefore,  in 
one  sense  regarded  as  an  acquired  character.  But  this  is  not  the 
meaning  attached  to  the  word  "acquired"  in  this  discussion.  What 
is  understood  by  an  acquired  chaiacter  here  is  a  somatic  change 
resulting  directly  from  an  environmental  influence  on  a  fully 
matured  individual.  Are  such  acquired  characters  transmitted  to 
an  offspring?  Are  they  hereditary? 

The  question  of  the  effect  of  environmental  influences  on  heredi- 
tary qualities  cannot,  it  seems  to  me,  be  put  as  a  general  proposi- 
tion, nor  any  answer  applied  with  equal  force  to  all  types  of  living 
organisms.  For  example,  when  environmental  influences  in  culture 
media,  temperature,  etc.,  alter  bacterial  forms  and  functions  and 
we  admit,  even  though  it  is  not  quite  certain,  that  these  charac- 
teristics are  newly  acquired,  we  are  simply  recording  phenomena 
11 


162  GENERAL  PATHOLOGY 

in  specific  types  of  the  lowest,  non-nucleated  fissiparous,  un- 
differentiated  single  cells.1 

It  does  not  justify  us  to  translate  these  observations  to  higher 
types  of  organisms,  especially  the  metazoa.  For  these  are  vastly 
different,  nucleated,  differentiated,  multicellular  individuals  with 
special  sex  cells  and  sex  territories  which  are  distinctly  separated 
from  the  rest  of  the  body  (Ray  Lankester). 

In  fact,  as  we  rise  higher  in  the  developmental  scale,  greater 
persistence  of  racial  characters  and  greater  resistance  towards  en- 
vironment become  noticeable.  With  differentiation  go  stability  and 
rigidity.  It  was  Weismann's  great  merit  to  point  out  clearly  that 
in  no  instance  in  higher  animal  life  had  a  direct  hereditary  environ- 
mental influence  been  noted,  and  that  characters  acquired  by  the 
soma  alone  had  never  been  proved  hereditary.  Mice  may  have 
their  tails  cut  off  for  generations  without  ever  producing  a  tailless 
variety.  The  Jews  have  practiced  circumcision  for  ages  without 
in  any  way  altering  the  size  of  foreskins.  Similar  somatic  altera- 
tions, experimentally  produced,  have  never  been  shown  to 
modify  hereditary  qualities. 

An  objection  to  the  weight  of  these  observations  may  justly  be 
made,  in  that  they  only  deal  with  local,  coarse  structural  modifi- 
cations and  not  with  general  environmental  influences  upon  the 
whole  organism  and,  therefore,  its  sex  cells.  Here  the  experimental 
investigations  of  Tower  must  be  mentioned  who,  by  changes  in 
temperature  and  humidity  on  the  larvae  of  certain  beetles  (potato- 
bug),  obtained  "mutants."  These  observations  need  repetition  and 
confirmation,  especially  as  being  true  mutants.  They  remain  so  far 
isolated  and  cannot  be  compared  to  self-fertilizing  plant  mutants  as 
described  by  de  Vries.  Moreover  they  resemble  types  still  seen 
within  the  normal  range  of  fluctuations  until  proved  otherwise  by 
experimental  testing.  The  same  uncertainty  surrounds  reports  of 
hereditary  transmission  of  still  very  obscure  immunity  reactions. 

1  Environmental  influences  have  limitations  even  in  bacteria.  Miss  M. 
Anderson  cultivated  in  my  laboratory  60  transplants  of  bacillus  coli  communior 
wtihout  any  sugar  media.  They  had  at  the  end  of  that  time  not  lost  any  of 
their  ability  to  ferment  glucose,  although  they  had  been  kept  in  sugar  free 
media  for  60  transplants.  Certain  functional  characteristics  seem,  therefore, 
to  be  deeply  rooted  in  the  simplest  forms  of  life. 


HEREDITY  163 

Attention  should  here  be  drawn  to  the  phenomenon  that  all 
evolution  proceeds  with  increasing  differentiation.  If  we  consider 
that  environment  not  only  shapes,  but  creates  new  types,  then  it  is 
difficult  to  understand  why  the  general  tendency  of  life  is  towards 
greater  differentiation.  Here  it  seems  more  reasonable  to  suppose 
that  the  ability  to  evolve  and  differentiate  is  part  and  parcel  of 
one  force  inherent  in  a  plasm  and  that  there  is  a  general  trend 
capable  of  proceeding  to  a  final  point  (final  species)  and  no 
further. 

It  has  sometimes  been  urged  that  inasmuch  as  exposure  of  ani- 
mals to  large  quantities  of  alcohol  vapors  or  the  continued  adminis- 
tration of  poisons,  like  lead,  lead  to  inferior  or  deficient  offspring, 
acquired  environmental  influences  are  transmitted.  But  in  these 
instances  we  are  not  dealing  with  unit  characters  or  qualities  at 
all,  but  with  pathological  development  from  direct  injury  to  the 
germ  plasm.  Quite  a  different  matter. 

The  difficulty  in  accepting  as  proof  experimental  evidence  and 
observations  which  have  been  recorded  in  favor  of  heredity  of 
acquired  environmental  characters  in  higher  types  of  life  is  the 
impossibility  of  ruling  out  latent  ancestral  qualities  and  individuals 
of  a  species  which,  as  in  the  important  phenomenon  of  convergence 
(Willey),  possess  variability  in  many  directions  and,  therefore, 
only  respond  to  an  environmental  call.1 

Furthermore,  it  must  be  pointed  out  that  some  so-called  "ac- 
quired qualities"  are  really  fluctuations,  that  is,  reversible,  and  only 
proof  of  wide  adaptation.  It  is  a  phenomenon  of  living  matter,  as  it 
rises  from  the  simple  to  the  complex,  to  more  and  more  resist  in- 
fluences on  its  germ,  and  to  develop  an  increasing  tendency  to  pres- 
ervation and  constancy.  Thus  the  race  is  strengthened,  and  by 
constant  mixture  of  closely  allied  qualities  it  preserves  its  indepen- 
dence and  varies  its  form. 

These  conclusions  have  received  strong  support,  first  by  the 
microbiochemical  observations  of  B.  A.  Macallum,  and  secondly  by 

1  The  term  "convergence"  is  applied  to  resemblances  among  animals  which 
are  not  due  to  direct  relationship  or  genetic  affinity,  in  other  words,  which 
are  not  derived  by  inheritance  from  common  ancestors,  but  which  result 
from  independent  functional  adaptation  to  similar  ends.  See  Willey:  "Con- 
vergence in  Evolution,"  p.  52. 


164  GENERAL  PATHOLOGY 

the  most  important  observations  of  de  Vries,  Bateson,  Morgan  and 
others  on  mutation.  The  persistence  of  the  germ  plasm  and  its 
relative  isolation  from  the  rest  of  the  body  is  accomplished  by  the 
cell  nucleus.  For  the  nucleus  is  an  exceedingly  resistant  structure 
to  the  introduction  of  other  substances.  It  does  not  know  inorganic 
salts,  fats,  carbohydrates  and  free  proteins,  all  of  which  are  unable 
to  pass  through  the  nuclear  membrane.  In  fact  the  nucleus  con- 
tains only  iron-containing  nucleo-proteids  which  are  synthetized 
within  the  cells  and  diffuse  into  the  nucleus.  The  nuclear  membrane 
is  permeable  only  for  these  iron-containing  nucleo-proteids.  His- 
tologically  these  nucleo-proteids  are  the  chromosomes,  the  carriers 
of  hereditary  qualities  and,  as  we  now  know,  even  of  sex  determi- 
nants. The  nuclear  membrane  protects  them  from  the  general  cell 
environment.  That  sports  and  variations  may  occur  by  changes  in 
the  permeability  of  the  nuclear  membrane  seems  conceivable  to 
Macallum,  but  has  not  been  demonstrated. 

Very  important  as  touching  upon  the  same  problem  are  the 
experimental  observations  on  mutation  in  relation  to  evolution. 
Evolutionists  are  divided  into  two  camps:  one  assumes  a  direct 
modifying  agency  of  the  environment,  producing  a  correspondingly 
useful  change  in  the  organization  (Neo-Lamarckians) ;  the  other 
assumes  fluctuating  variations  with  gradual  stability  and  persist- 
ence by  natural  selection  (Darwinians).  It  was  especially  the 
merit  of  a  botanist,  de  Vries,  to  point  out,  backed  by  strong 
evidence,  that  species  and  varieties  occur  by  mutation  which 
suddenly  produce  new  forms,  not  gradually  and  slowly  by  the 
natural  selection  as  claimed  by  Darwin,  Wallace  and  their  followers. 

Thus  also,  recent  observations,  especially  of  Morgan  on  certain 
of  the  insects,  as  in  the  fruit  fly  (Drosopbila  ampelophila),  have 
shown  that  "mutations  in  every  part  of  the  body  arose  suddenly 
and  independently  and  that  these  bear  no  historic  relations,  al- 
though, if  they  are  arbitrarily  arranged  in  order,  for  example,  in 
the  size  of  wings,  an  almost  complete  series  of  gradual  change  may 
be  established.  In  fact,  none  of  these  mutations  has  any  relation  to 
another;  each  originates  independently.  A  serial  arrangement  would 
give  a  totally  false  idea  of  the  way  different  types  have  arisen,  and 
any  conclusion  based  on  the  existence  of  such  a  series  might  very 


HEREDITY  165 

well  be  erroneous,  for  the  fact  that  such  a  series  exists  bears  no 
relation  to  the  order  in  which  its  members  have  appeared." 

What  then  does  natural  selection  do?  In  the  words  of  Arthur 
Harris:  "Natural  selection  may  explain  the  survival  of  the  fit- 
test, but  it  cannot  explain  the  arrival  of  the  fittest,"  or,  as  Mor- 
gan expresses  it:  "Evolution  has  taken  place  by  incorporation 
into  the  race  of  those  mutations  that  are  beneficial  to  the  life 
and  reproduction  of  the  organism." 

"Natural  selection,  as  here  defined,  means  both  the  increase  in 
the  number  of  individuals  that  result  after  beneficial  mutations 
have  occurred  (owing  to  the  ability  of  living  matter  to  propagate), 
and  also  that  this  preponderance  of  certain  kinds  of  individuals  in  a 
population  makes  some  further  results  more  probable  than  others. 
More  than  this  natural  selection  cannot  mean,  if  factors  are  fixed 
and  are  not  changed  by  selection."  To  this  must  be  added  that 
inbreeding  or  selection  may  strengthen  certain  hereditary  unit 
characters,  although  this  strengthening  of  some  gradually  weakens 
others.  Renewed  mixture  of  different  characters  appears  essential 
to  retain  the  vigor  of  a  race. 

Having  thus  arrived  at  the  conclusion  that  multicellular,  complex 
forms  of  life,  such  as  animals  represent,  are  not  influenced  by  their 
enrivonment  to  develop  new  hereditary  characters,  but  that 
variations  arise  from  as  yet  unexplained,  rapid  mutations,  we  are 
particularly  interested  from  the  standpoint  of  pathology,  to  inquire 
further  into  the  inheritance  of  variations  and  the  mechanism  of 
inheritance.  It  is  here  necessary  to  recall  shortly  certain  embryo- 
genetic  phenomena. 

It  has  been  stated  that  hereditary  qualities  are  carried  by  the 
chromosomes  of  the  nucleus  in  sex  cells  and  it  is  well  known  that 
the  offspring  of  two  parents  carries  by  amphymixis  male  and  fe- 
male elements  or  unit  characters.  It  is  important  to  recall  here 
that  before  fertilization,  male  and  female  sexual  cells  undergo  a 
process  of  reduction  in  their  chromosomes.  By  repeated  division 
these  are  reduced  to  one-half  of  their  original  number.  The  signifi- 
cance of  this  reduction  is  not  clear.  Strassburger  suggested  a  reten- 
tion of  ancestral  structures  only.  At  any  rate  such  reduced  cells 
are  ready  for  sexual  union  and  are  known  as  gametes. 


166  GENERAL  PATHOLOGY 

After  fertilization  the  sexual  cells,  by  fusion  of  an  equal  number 
of  chromosomes  from  both  parents,  again  possess  the  normal  num- 
ber of  chromosones,  but  necessarily  of  two  sex  or  unit  characters, 
so  that  the  offspring  contains  50  per  cent,  male  and  50  per  cent, 
female  elements.  Such  a  cell  is  a  zygote  and  the  number  of  chro- 
mosomes for  the  zygotes  are  specific  for  different  species.  Sex  cells 
which  contain  different  unit  characters  are  spoken  of  as  heterozy- 
gotes,  while  those  containing  uniform  unit  characters  are  known 
as  homozygotes. 

Now  it  is  of  utmost  importance  to  know  how  hereditary  qualities 
are  handed  to  posterity.  Is  this  done  in  an  arbitrary,  lawless  manner, 
or  do  the  phenomena  of  hereditary  transmission  conform  to  a 
definite  mechanism?  May  qualities  arise  in  an  offspring  which  are 
not  ancestral? 

The  greatest  discovery  in  this  field  was  made  by  the  Austrian 
monk,  Mendel,  between  1857-1865  who,  while  a  contemporary  of 
Darwin,  remained  unknown  to  him  or  any  scientist  until  de  Vries 
rediscovered  his  work  and  recognized  his  results  as  Mendel's  laws 
of  heredity.  Mendel,  in  investigations  carried  on  in  order  to  im- 
prove certain  kinds  of  garden  peas  in  the  monastery  of  Briinn, 
discovered  the  important  phenomena  of  descent  by  segregation 
through  dominance  and  recession  and  of  reassortment.  He  and 
subsequent  investigators  chose  the  simplest  constant  unit  char- 
acters for  observation:  length,  height  and  color.  In  them  the  fate 
of  unit  characters  may  be  easily  followed  through  inbreeding 
without  interference  from  other,  more  complicated  hereditary 
qualities  of  a  much  involved  ancestral  series. 

By  mating  a  giant  and  a  dwarf  pea,  Mendel  found  that  the  first 
offspring  resembled  only  one  of  the  parents,  the  tall,  and,  therefore 
dominant  character.  But  this  tall  offspring  had  not  lost  the  dwarf 
quality.  This  remained  only  hidden  or  recessive,  for  in  the  second 
generation  (inbred),  there  appeared  both  giant  and  dwarf  descend- 
ants in  the  proportion  of  3  giants  to  i  dwarf.  Of  these  25  were  pure 
dominants  (remained  giants  on  continued  inbreeding;  were  homo- 
zygotes), 25  per  cent,  remained  pure  recessives;  while  50  per  cent, 
were  impure  dominants  (heterozygotes).  These,  on  repeated  breed- 
ing, split  again  in  ratio  of  3  giants  to  i  dwarf.  Similar  results 


HEREDITY  167 

were  obtained  by  mating  yellow  and  green  peas.  The  first  hybrid 
was  yellow,  the  subsequent  generation  green  and  yellow,  again  in 
proportion  of  3  yellow  to  I  green,  and  so  on. 

The  importance  of  this  investigation  is  at  once  apparent,  for  it 
demonstrates  a  definite,  orderly  mechanism  of  descent — the  fact 
that  hereditary  characters  are  capable  of  segregation,  and,  that 
hereditary  qualities,  although  hidden,  are  not  lost,  but  reappear  in 
future  generations. 

Not  all  union  of  hereditary  characters  leads  at  once  to  dominance 
of  one  over  the  other.  It  is  well  known  that  there  are  instances  of 
permanent  and  temporary  blending.  This  seems  to  occur  by  mating 
dominant  or  positive  characters.  Correns,  for  example,  mated  a  red 
and  white  mirabilis  jalapa  (positive  white  color,  not  white  from 
absence  of  color  as  in  albino)  and  obtained  a  pink  offspring.  Self- 
fertilized,  this  offspring  split,  segregated  to  one  pure  white  two 
pink  and  one  pure  red  plant  (1:2:1).  Of  these  red  and  white  con- 
tinued pure,  while  the  pink  segregated  again  in  the  proportion  of 
1:2:1,  that  is,  Mendelize  in  the  second  generation.  There  are,  how- 
ever, as  yet  poorly  understood  exceptions  in  which  blending  con- 
tinues and  only  occasionally  for  unknown  reasons,  segregates. 
Finally,  in  the  mating  of  a  heterozygote  with  a  homozygote  off- 
spring in  proportion  of  1:1,  heterozygote,  homozygote,  result. 

The  important  and  impressive  point  in  these  experiments  re- 
mains the  establishment  of  the  principle  of  segregation  in  heredi- 
tary transmissions.  But  this  is  not  the  only  far-reaching  discovery 
of  Mendel.  In  an  equally  important  second  set  of  experiments  he 
established  the  principle  of  independent  assortment. 

If  a  yellow,  round  pea  is  crossed  with  one  that  is  green  and  wrin- 
kled, all  offspring  are  yellow  and  round.  Inbred  these  give  9  yellow 
round,  3  green  round,  3  yellow  wrinkled,  i  green  wrinkled.  All 
the  yellow  are  to  the  green  as  3 :  i ;  all  round  to  the  wrinkled  as  3 :  i ; 
but,  as  will  have  been  noted,  some  yellows  are  now  wrinkled  and 
some  green  are  now  round.  In  other  words,  characters  have  recom- 
bined  while  at  the  same  time  for  each  pair  of  characters  separately, 
the  results  are  in  accord  with  Mendel's  law  of  segregation. 

Such  and  similar  series  discovered  in  animals  demonstrate  the 
recombination  of  hereditary  characters  of  different  organisms  and 


i68  GENERAL  PATHOLOGY 

assortments  in  the  germ  cells  according  to  a  definite  law.  We 
therefore  see  that  the  individual  in  any  serial  tree  is  not  a  fixed 
unit  in  heredity,  but  only  the  somatic  sum  of  developed  segrega- 
tions and  assortments  with  still  others  existing  undeveloped  in  the 
germ  cells. 

It  must  be  recalled  that  in  these  observations  we  are  dealing  only 
with  the  simplest  mixtures  of  elementary  unit  characters.  In  higher 
animals,  and  especially  in  man,  conditions  are  necessarily  much 
more  involved  by  a  long  ancestral  series  of  assortments  and  segre- 
gations. Moreover  it  must  be  emphasized  once  more  that  hereditary 
qualities  are  only  latent  and  that  their  development  and  shape  to 
specific  organic  expressions  are  dependent  upon  environmental  calls 
and  actions.  Environment  activates  latent  qualities. 

However,  it  is  plain  that  an  offspring  can  contain  only  the  char- 
acters handed  to  him  by  his  ancestral  tree;  that  is  his  endowment. 
He  is,  therefore,  determined  by  his  ancestors,  but  molded  by  his 
environment.  Individual  differences  seem,  therefore,  to  be  due 
mainly  to  the  tremendous  possible  number  of  assortments,  segre- 
gations, blends  and  dominants.  It  may  be  compared  to  the  innu- 
merable melodies,  ranging  from  the  sublime  to  the  ridiculous,  which 
may  be  composed  by  changing  sequence  and  rhythm  of  only  the 
eight  tones  and  their  halves  which  comprise  the  octave. 

Thus  it  becomes  intelligible  that  certain  dispositions  to  disease 
or  certain  abnormal  body  constitutions,  such  as  those  of  color- 
blindness, hemophilia  (bleeder),  polydactylism  etc.,  are  handed 
from  one  generation  to  another  in  a  definite  mechanism  and 
by  members  which  themselves  escape.  A  color-blind  father,  for 
example,  transmits  through  his  daughters  his  family  constitu- 
tion to  half  his  grandsons,  but  to  none  of  his  granddaughters.  In 
the  few  instances  of  color-blind  mothers  reported,  who  married 
normal  husbands,  the  sons  have  inherited  it  from  the  mother. 
Very  similar  are  the  inheritance  conditions  in  hemophilia,  in 
which  this  constitution  is  also  transmitted  through  females  who 
generally  themselves  escape. 

The  other,  practically  important,  point  is  evident.  It  is  impos- 
sible to  predict  the  character  of  an  offspring  from  the  physical 
appearance  of  the  parents.  No  one  can  say  what  ancestral  qualities 


HEREDITY  169 

may  be  hidden  in  sex  cells  and  what  may  appear  by  segregation  or 
assortment  in  a  future  generation.  Fine,  physically  fit  bodies 
(parents)  may  not  necessarily  give  rise  to  an  equally  fine  descend- 
ant, and  vice  versa. 

This  is  true  not  only  on  the  physical,  but  on  the  mental  side. 
Genius  may  come  from  unsuspected  sources.  But,  even  if  it  arises 
from,  and  in,  most  unfavorable  environment  and  from  parents 
themselves  of  lower  type,  the  genius  is  not  their  own  product,  but 
a  necessary  member  of  a  series  arising  from  a  lawful  combination 
and  segregation  of  ancestral  qualities. 

We  may,  therefore,  conclude  that  as  far  as  hereditary  qualities 
are  concerned,  evidence  points  to  a  fixed  endowment  of  an  individ- 
ual by  his  ancestral  tree.  No  conclusive  evidence  has  so  far  been 
furnished  that  environmental  influences  do  in  metazoa  anything 
but  shape  and  develop  latent  qualities  and  that  natural  selection 
goes  beyond  strengthening  them. 

It  is  futile  and  unjustifiable  in  view  of  what  we  know,  and  in 
ignorance  of  as  yet  so  many  unsolved  problems,  to  attempt  any 
artificial  interference  with  human  racial  development. 


BOOK  II 

PATHOLOGICAL  ANATOMY  AND 
HISTOLOGY  AND  PATHOGENESIS 


CHAPTER  I 
INTRODUCTION 

ALL  life  and  all  expressions  of  life  are  dependent  upon  cell  activity. 
The  cell  is,  as  Virchow  established  it,  the  anatomical  and  func- 
tional unit.  Physiological  life  requires  proper  balance  between  the 
various  forms  of  energy  and  cell  reactions;  these  constitute  the 
external  and  internal  factors  of  life.  The  various  forms  of  energy 
which  affect  the  cell  are  termed  stimuli,  and  stimuli  are,  therefore, 
causes  of  release  in  organic  systems  (Albrecht) . 

Cell  systems  (protoplasm)  at  rest  are  in  equilibrium.  An  outside 
energy  (stimulus)  which  upsets  this  equilibrium  by  either  physical 
or  chemical  means,  releases  certain  constituents  and  sets  free  as- 
sociated functions,  translates,  therefore,  latency  into  actual  oc- 
currence. Thus,  for  example,  lipoid  solvents  in  certain  high  dilutions 
disturb  or  upset  the  protoplasmic  emulsion  by  withdrawal  of  lipoids 
and  give  rise  to  processes  which  initiate  growth  and  proliferation. 

Cell  functions  are,  therefore,  phenomena  or  attributes  of  physico- 
chemical  cell  reactions  and  the  ability  of  a  cell  to  enter  into  relation 
with,  and  respond  to,  stimuli  is  called  "irritability,"  a  term  origi- 
nally introduced  by  the  great  physiologist  Haller  to  designate  the 
contractile  response  of  muscle  to  certain  outside  influences,  the 
"irritants."  As  long  as  stimuli  and  cell  reactions  remain  within 
range  of  adaptation,  in  a  manner  that  cell  structure  is  not  perma- 
nently altered  but  rapidly  returns  to  its  equilibrium,  life  is  rela- 
tively stable  or  physiological.  But  lasting  disproportion  between 
stimuli  and  cell  reactions  beyond  physiological  adaptation  are 
followed  by  profound  alterations  in  protoplasmic  structure  and, 
therefore,  cell  functions.  This  is  pathological  life.  The  dispropor- 
tion may  be  due  to  excessive  stimulation  (active)  or  due  to  lack 
of  stimulation  (passive). 

Pathological  stimuli  or  irritants  are,  therefore,  those  for  which 


174  GENERAL  PATHOLOGY 

the  elasticity  of  cell  response  no  longer  suffices.  In  this  connection 
it  must  be  appreciated  that  cell  protoplasm  is  of  different  quality 
in  different  cell  territories  (organs)  and  also  in  various  age  periods. 
An  embryonic  cell  has  a  different  constitution  and  is  more  labile 
in  its  construction  than  an  adult  or  senile  cell.  Thus  also,  liver 
muscle  and  kidney  cells  are  specific  in  protoplasmic  qualities  and 
functions.  What,  therefore,  may  constitute  a  physiological  stimu- 
lus, or  may  still  come  within  a  physiological  range  in  one  cell,  may 
cause  no  response  in  another  and  may  even  act  as  a  pathological 
stimulus  in  a  third.  We  are  to-day  still  quite  ignorant  of  the 
nature  of  specific  protoplasmic  quality  although  we  know  that  it 
exists,  and  our  knowledge  is  confined  to  the  phenomena  of  coarse 
general  cell  life. 

It  may  be  advanced  as  a  general  proposition  that  pathological 
irritants  produce  two  main  alterations  in  cells:  first,  passive,  repre- 
sentative of  the  effect  on  the  cells;  this  is  spoken  of  as  injury, 
because  physiological  response  is  thereby  altered,  lowered  or 
abolished;  second,  reactive,  the  reply  of  the  cells  to  the  pathological 
irritant;  both  constitute  disease.  Depending  upon  the  quality  and 
degree  of  the  irritation  and  the  effects  of  the  local  and  general 
environment,  either  passive  or  reactive  processes  predominate 
and  control  the  pathological  picture. 

Structural  changes  are  for  the  most  part  visible,  grossly  or  micro- 
scopically. But  at  times  they  are  so  delicate  and  fine  that  we  are 
unable  to  recognize  them  and  observe  only  the  accompanying 
functional  disturbance.  As  our  knowledge  and  mechanism  of 
observations  improve  many  of  these  so-called  functional  diseases 
are  recognized  in  their  structural  basis. 

The  whole  field  of  general  pathological  morphology  and  patho- 
genesis  may  be  divided  into  four  great  chapters : 

I.  Pathological   changes   in  the  cells  (nutritive  disturbances) 

(1)  regressive;  atrophy,  degeneration,  necrosis;  (2)  progressive: 
hypertrophy,  regeneration. 

II.  Pathological  changes  in  local  cell  relations:  (i)  inflammation; 

(2)  pathological  growth,  tumors. 

III.  Pathological  changes  in  general  cell  interrelation:  (i)  cir- 
culatory disturbances:  hyperemia,  anemia,  thrombosis,  embolism, 


INTRODUCTION  175 

infarction,  hemorrhage,  shock,  pathological  transudation,  edema; 
(2)  disturbances  of  internal  secretion;  (3)  fever. 

IV.  General  somatic  death. 

The  problem  which  faces  us  in  this  study  is  the  determination  of 
anatomical  changes  in  their  dynamic  values  and  relations.  Not  as 
fixed  structual  deviations,  but  as  expressions  of  processes.  It  will  be 
our  duty  to  determine  what  is  common  in  their  origin,  sequence 
and  results,  what  is  variable,  how  they  are  related  to,  and  compare 
with,  physiological  life  and  each  other,  and  what  is  their  nature 
and  position  in  life.  Viewed  from  this  standpoint  pathological 
anatomy  ceases  to  be  dead  or  "dead  house "  experience.  It  is  an 
experimental  science  in  which  the  problem  is  set  by  nature  itself 
in  a  manner  of  time  and  environment  which  goes  beyond  artificial 
experimentation.  The  artificial  experiment  may  supplement  it  for 
the  elucidation  of  certain  phases,  but  it  can  never  give  us  the 
disease.  Pathological  anatomy  remains,  therefore,  the  pillar  of 
pathological  science. 


CHAPTER  II 

PATHOLOGICAL  CHANGES  IN  CELLS  (NUTRITIVE  DIS- 
TURBANCES) 

I.    REGRESSIVE   CHANGES 

I.  ATROPHY  (from  d  =  negative,  and  rpo<pia  =  to  nourish).  By 
atrophy  is  understood  a  diminution  in  size  of  cells  and  organs 
through  loss  of  protoplasmic  elements  and  in  cell  number  (numeri- 
cal atrophy).  Pure  atrophy  is  essentially  a  quantitative  reduction 
in  which  the  quality  of  the  cell  is  not  essentially  altered.  But  as  the 
process  advances  certain  qualitative  changes  are  added  (fat  in- 
filtration, pigmentation,  etc.)  and  ultimately  cell  death  ensues. 
These  qualitative  disturbances,  however,  follow  and  are  the  result 
of  atrophy.  They  are  secondary,  variable,  and  not  an  essential 
part  of  the  atrophic  process. 

Not  all  atrophy  is  pathological.  The  disappearance  of  certain 
embryonic  structures,  the  atrophic  changes  in  sexual  organs  after 
the  menopause,  senility  and  others,  still  come  within  physiological 
performance,  but  they  merge,  often  imperceptibly,  into  pathologi- 
cal lesions.  Atrophy  must  be  distinguished  from  hypoplasia  or 
underdevelopment,  in  which,  through  inhibitory  factors,  organs 
never  reach  their  normal  size  and  construction. 

The  causes  of  atrophy  are  general  or  local.  The  most  important 
are,  first,  inanition,  from  interference  with  food  supply.  Here  all 
the  tissues  of  the  body  suffer,  but  unevenly  and  gradually.  Primarily 
fat  tissue  and  musculature  suffer,  then  parenchymatous  organs; 
bones  and  central  nervous  system  last  and  least.  Secondly,  in- 
activity, when  the  general  or  local  functions  of  an  organ  are  dimin- 
ished or  suspended  (muscles,  glands,  etc.),  cells  and  organs  grow 
smaller.  This  must  be  attributed  largely  to  lowering  of  cell  metab- 
olism, for  functional  activity  furnishes  heat  and  energy  by  acti- 
vating forces  for  cell  life  and  preservation.  Thirdly,  nervous 

176 


PATHOLOGICAL  CHANGES  IN  CPUS  177 

influences,  either  central  or  peripheral.  The  influence  of  the  nervous 
system  on  the  integrity  of  cells  and  organs  is  still  quite  obscure  and 
referred  to  as  trophic.  It  is  probably  complex,  consisting  of  several 
interlocked  influences.  Thus,  the  nervous  system  controls  not  only 
metabolism  but  function,  and  paralysis  of  nerves  or  nervous  centers 
has,  therefore,  a  double  effect  on  cell  life. 

While  these  three  causes  may  arise  from  general  body  disturb- 
ances, they  may  also  depend  upon  local  conditions  (such  as  pres- 
sure, interference  with  circulation,  peripheral  nervous  control). 
Atrophy  usually  involves  whole  organs  uniformly:  these  diminish 
in  size  and  preserve,  except  in  extreme  cases  or  unusual  local 
atrophies,  their  shape.  The  atrophic  process  is  generally  slow  in 
progress;  towards  the  end,  when  qualitative  disturbances  make 
their  appearance,  somewhat  more  rapid.  Microscopically  the  in- 
dividual cells  appear  smaller,  but  definite,  widely  separated.  Nuclei 
remain  well  preserved  until  late,  but  are  poor  in  chromatin. 

As  the  process  advances,  the  reduction  in  protoplasm  interferes 
more  and  more  with  cell  metabolism  and  certain  qualitative 
changes  are  added.  The  most  frequent  is  abnormal  pigmentation, 
that  is  precipitation  of  usually  invisible  protoplasmic  pigment 
(muscle,  liver,  etc,).  Then  appear  fat  drops  as  expression  of  the 
increasing  interference  with  the  oxidation  ability  of  the  celL  Fi- 
nally occurs  in  the  loose,  remaining  reticular  tissue  serous  or  gelat- 
inous material.  Reticulum  and  intercellular  connective  tissue  are 
generally  made  relatively  prominent,  but  not  increased. 

Restitution  to  integrity  in  atrophic  cells  is  quite  possible  in  early 
stages  when  the  cause  or  causes  are  removed.  How  far  restitution 
may  occur  in  advanced  cases  is  not  yet  determined.  Occasionally 
the  atrophying  cells  proliferate,  new  nudei  appear  in  cells  and  free: 
even  nodular  growths  of  regenerating  cells  in  more  or  less  atypical 
fashion  may  make  an  appearance  (this  is  well  illustrated  in  the 
liver  during  the  atrophy  of  chronic  venous  congestion).  Ultimately 
atrophic  cells  waste  completely,  die,  and  their  protoplasmic  and 
nuclear  remains  are  visible  as  granular  structureless  material,  or 
they  are  dissolved  in  tissue  fluids  and,  at  least  partly,  removed. 

2.  DEGENERATIONS.  The  term  degeneration  is  applied  to  quali- 
tative changes  in  the  protoplasm  of  cefls  by  which  their  anatomical 


178  GENERAL  PATHOLOGY 

and  physiological  character  and  functions  are  essentially  disturbed 
and  altered.  These  are  brought  about  by  deep-seated  physical  and 
chemical  revolutions  in  the  cell  protoplasm  which  lead  to  an  entirely 
new  arrangement  of  its  constituents  and  at  times  to  the  appearance 
of  new  substances. 

In  order  to  understand  this  properly  it  is  necessary  to  recall 
once  more  the  constitution  of  normal  protoplasm.  Cell  protoplasm 
is  not  a  rigid,  uniform  substance,  or  even  mixture  of  substances,  but 
a  fluid  aggregate  which  allows  intercourse  with  the  outside  and 
between  nucleus  and  plasma.  In  our  modern  conception  protoplasm 
is  regarded  as  a  combination  of  not  directly  miscible,  but  tenacious 
fluids  held  together  in  form  of  an  emulsion. 

Biitschli,  from  optical  considerations,  regarded  protoplasm  as  a 
honeycomb  structure  (Wabenstruktur)  in  which  fluid  substances 
are  held  together,  and  at  the  same  time  separated,  by  a  non-soluble 
network.  But  the  recent  investigations  of  Weimarn  indicate  that 
this  is  a  secondary  structure,  due  to  pressure  exerted  on  the  proto- 
plasm, and  may  be  produced  in  similar  fashion  by  superimposed 
amorphous  and  crystalline  substances. 

We  only  know,  so  far,  that  protoplasm  is  an  emulsion  into  the 
formation  of  which  enter  colloidal  proteins,  carbohydrates,  fats  of 
neutral  and  lipoid  constitution,  with  other  specific  cell  substances 
which  determine  the  character  of  the  cell.  The  metabolism  and 
exchange  of  this  emulsion  depends  upon  various  forces,  princi- 
pally osmotic  pressure,  the  colloidal  properties  of  the  cell  con- 
stituents, and  surface  tension  (surface  permeability).  These  also 
maintain  the  cell  constitution  and  that  of  nucleus  and  plasma.  All 
outside  energies  (that  is,  irritants)  which  reach  the  cell,  influence, 
as  has  already  been  explained,  the  cell  by  releasing  certain  of  its 
physico-chemical  latencies,  and  this  is  spoken  of  as  stimulation. 

Thus  we  can  recognize  three  general  fundamental  groups  of 
stimuli,  which  were  first  defined  by  Virchow,  namely  those  re- 
leasing nutrition,  those  releasing  function  and  those  releasing 
growth;  nutritive,  functional  and  formative  stimuli.  All  outside 
energies  which  irritate  or  stimulate  cells  beyond  physiological  rapid 
adaptation  and  return  to  equilibrium  upset  the  cell  constitution, 
lead,  therefore,  to  disorganization  of,  and  abnormal  physical- 


PATHOLOGICAL  CHANGES  IN  CELLS  179 

chemical  changes  in  protoplasm  and  thus  lower,  abolish  or  pervert 
physiological  functions.  Such  cells  are  degenerated  cells. 

Degenerations  may  be  classified  according  to  their  chief  mor- 
phological changes  in  cell  constituents. 

I.  Albuminous  degenerations:  (a)  cloudy  swelling  (parenchyma- 
tous  degeneration) ;  (6)  mucoid  degeneration ;  (c)  colloid  degenera- 
tion; (d)  hyaline  degeneration;  (e)  amyloid  degeneration. 

II.  Fatty  metamorphoses:  (a)  pathological  fat  infiltration;  (6) 
fatty  disorganization  or  degeneration. 

III.  Glycogen  infiltration. 

IV.  Calcareous  infiltration. 
V.  Pigmentary  infiltration. 

I.  Albuminous  Degenerations,  (a)  Cloudy  Swelling,  Parencbyma- 
tous  Degeneration.  Our  knowledge  of,  and  the  terms,  cloudy  swell- 
ing and  parenchymatous  degeneration  in  the  modern  sense  date 
from  Virchow.  He  designated  thus  a  cell  degeneration  affecting 
more  particularly  parenchyma  cells,  in  which  enlargement  due  to 
swelling  and  cloudiness  of  protoplasm  form  the  essential  morpho- 
logical constituent.  It  is  a  very  frequent  degeneration,  the  result 
of  the  effects  of  poisons  or  bacterial  toxines. 

Cells  thus  affected  are  seen  microscopically  to  lose  their  definite 
outlines  and  structure,  but  appear  succulent,  plump  and  turbid. 
On  closer  inspection  numerous  coarse  granules  are  conspicuous 
in  the  cloudy  cell  body  (granular  degeneration  of  some  writers). 
These  granules  are  insoluble  in  weak  acetic  acid  (2  to  5  per 
cent.)  or  alkalies  (2  per  cent.  KOH)  and  are  of  proteid  composi- 
tion. Large  hyaline,  highly  light  refractive  bodies  are  also  seen. 
The  nucleus  is  affected  sooner  or  later,  but  may  escape  in  lighter, 
rapidly  regressing  lesions.  It  suffers  either  from  chromatolysis, 
i.e.,  centrifugal  loss  (solution)  of  its  chromatin,  which  is  discharged 
into  the  protoplasm  or,  from  pyknosis,  i.e.,  centripetal  condensa- 
tion and  fusion  of  chromatin  with  loss  of  fluid  nuclear  constituents. 
Finally  occurs  karyorrhexis,  i.e.,  rupture  of  the  nuclear  membrane, 
often  preceded  by  indentations  and  constrictions  of  its  body  and 
loss  of  the  nuclear  scaffold.  These  phenomena  are  largely  the  result 
of  surface  tension  changes  in  the  cell  from  actions  of  an  irritant, 
(see  below). 


i8o  GENERAL  PATHOLOGY 

Regeneration  of  nucleus  and  cell  is  possible  as  long  as  the  nuclear 
structure,  the  scaffold,  remains  intact.  Complete  nuclear  destruc- 
tion (karyorrhexis)  is,  of  course,  followed  by  lasting  cell  loss.  When 
the  nucleus  escapes  serious  injury  cell  reconstruction  is  rapidly 
accomplished. 

The  explanation  of  the  nature  of  parenchymatous  degeneration 
is  a  difficult  problem,  as  it  necessarily  involves  the  still  obscure 
points  of  protoplasmic  constitution.  It  includes  two  important 
questions :  What  is  the  origin  and  significance  of  cell  swelling,  and, 
what  is  the  derivation  and  nature  of  the  coarse  granules?  Virchow 
was  the  first  to  offer  an  intelligent,  well  thought  out  explanation. 
To  him  parenchymatous  degeneration  appeared  in  the  light  of  over- 
nutrition  of  cells :  as  the  result  of  excessive  stimulation  or  irritation 
the  cell  assimilates  an  excess  of  nutrient  material  which  it  cannot 
take  care  of.  Consequently  this  precipitates  in  the  form  of  granules ; 
the  injured  cell  protoplasm  is  unable  to  dispose  of  this  excessive 
nutrient  material  and  degenerates. 

Pathologists  after  Virchow  did  not  add  much  to  a  better  under- 
standing of  the  lesion,  until  Galeotti,  based  on  Naegeli's  conception 
of  protoplasm,  explained  the  coarse  granular  appearance  of  the 
cell  body  as  a  change  in  aggregate  condition  of  the  protoplasm  and 
regarded  them  as  first  evidence  of  cell  necrosis.  Subsequent  inves- 
tigations of  Landsteiner  and  Orgler  led  them  to  similar  views. 
With  our  present  somewhat  more  extended  knowledge  of  colloidal 
processes  and  of  the  means  through  which  the  cell  enters  into 
communication  with  the  outside,  we  can  define  the  processes  of 
parenchymatous  degeneration  with  greater  precision. 

It  is  certain  that  the  assimilation  of  fluid  to  which  the  swelling 
is  due,  as  well  as  the  subsequent  appearance  of  the  coarse  granules, 
are  the  results  rather  than  the  cause  of  parenchymatous  degene- 
ration. For  the  first  requisite  for  swelling  of  cells,  which  are,  as  we 
have  seen,  emulsified  colloidal  systems,  is  resorption  of  excessive 
fluid.  This  depends  upon  changes  in  the  osmotic  properties  of 
cells,  whereby  their  hydrophylic  capacity  is  increased  and  fluid, 
which  is  ordinarily  prohibited  from  doing  so,  is  allowed  to  enter. 
The  first  step  is,  therefore,  increase  of  surface  permeability  in  cells. 
It  is  plain  that  this  is  the  direct  result  of  (solvent?)  action  of  an 


PATHOLOGICAL  CHANGES  IN  CELLS  181 

irritant  on  the  cell  surface  and  that,  by  subsequent  entrance  of  the 
irritant  into  the  cell,  the  normal  state  of  emulsion  is  attacked.  The 
coarse  granular  appearance  which  immediately  follows  this  swell- 
ing cannot,  for  this  reason,  be  regarded  as  simple  precipitation  of 
food,  but  as  a  new  protoplasmic  arrangement  in  which  emulsoids 
are  thrown  out  of  the  emulsion  and  precipitated  to  suspensoids. 
This  explains  the  close  physical  resemblance  between  cloudy 
swelling  and  boiled  tissues.  Boiling  also  converts  emulsoids  to 
suspensoids. 

The  phenomena  of  parenchymatous  degeneration  are,  therefore, 
the  morphological  expression  of  a  pathological  protoplasmic 
rearrangement.  The  nature  of  the  lesion  is  a  disturbance  of  the 
normal,  physiological  cell  systems  which  leads  to  upset  and  dis- 
organization of  the  protoplasmic  emulsion.  The  cell  is  thus  injured. 
These  views  are  confirmed  by  the  later  fate  of  this  degeneration. 
For,  if  these  cells  are  not  speedily  allowed  to  regenerate,  but  patho- 
logical environment  and  cell  injury  continue,  the  degeneration 
proceeds  to  further  cell  disintegration.  This  is  morphologically  ex- 
pressed first,  by  liberation  of  fatty  substances  originally  held 
concealed  in  cell  emulsion;  secondly,  the  appearance  of  vacuoles; 
finally,  by  complete  coagulation  and  autolysis  with  cell  death. 
The  details  of  these  final  stages  and  changes  are  treated  under 
fatty  metamorphoses  and  necrosis. 

It  is  noteworthy  in  this  connection  that  it  is  possible,  as  shown 
by  the  author,  to  reproduce  the  picture  of  parenchymatous  de- 
generation in  freshly  removed  normal  organs,  kidney  or  liver,  by 
exposing  thin  sections  to  the  action  of  lipoid  solvents,  ether 
water,  for  example.  The  cells  are  then  seen  to  swell,  become  darker, 
coarsely  granular  and  ultimately  delicate  fatty  granules  appear. 
Here  also  the  evidence  points  to  upset  of  the  cell  emulsion  by  the 
solvent  with  increase  of  water  contents  of  the  cell  and  precipitation 
of  granular  suspensoids  from  the  normal  emulsion. 

C.  Demel  has  shown  that,  by  modification  of  the  osmotic  condi- 
tions of  cells,  some  of  the  characteristic  features  of  parenchymatous 
degeneration  could  be  produced.  H.  J.  Hamburger  and  M.  Fischer 
have  also  produced  similar  pictures  by  exposing  cells  to  the  effects 
of  weak  concentrations  of  acid.  Hamburger  attributes  the  swelling 


1 82  GENERAL  PATHOLOGY 

to  the  increase  of  osmotic  pressure  brought  about  by  acid  in  the 
cells.  M.  Fischer  considers  the  swelling  a  result  of  water  absorption 
by  one  cell  protein  through  the  acid,  while  he  holds  that  the  granu- 
lar precipitation  is  due  to  dehydration  of  another  protein.  His  chief 
support  for  this  view  is  the  experiment  of  pouring  a  solution  of 
casein  into  20  per  cent,  gelatine,  allowing  this  to  harden  and  expos- 
ing this  solid  mixture  to  the  action  of  dilute  acid.  The  swelling 
which  follows  he  attributes  to  the  gelatine,  and  the  simultaneous 
cloudiness  to  precipitation  of  casein.  This  is,  in  my  opinion,  a  too 
one-sided  and  narrow  interpretation  of  the  process  of  parenchyma- 
tous  degeneration,  for  we  are  dealing  in  cells  not  only  with  protein 
mixtures,  but  very  complex  emulsions;  so  complex  that  they  give 
to  cells  specificity  of  form  and  function. 

Thus,  experience  teaches  that  not  all  cells  are  equally  predisposed 
to  cloudy  swelling.  Some,  like  liver  and  kidney  cells,  are  decidedly 
more  susceptible  to  certain  poisons  than  others.  Moreover  certain 
irritants  (infections  and  toxines)  produce  the  lesion  more  readily  in 
some  types  of  cells  than  in  others.  To  attribute  the  whole  process 
to  acid  contents  in  the  cells  alone  is,  therefore,  not  sufficient, 
especially  since  increased  H  ion  concentration  in  tissues  may  exist 
without  cloudy  swelling.  It  appears,  therefore,  that  the  primary 
essential  factor  which  increases  the  hydrophylic  capacity  of  the 
cell  and  initiates  swelling  and  precipitation  is  an  irritant  which,  by 
altering  surface  permeability,  gains  entrance  into  the  cell,  and  thus 
upsets  the  physiological  cell  emulsion.  Anatomical  as  well  as  experi- 
mental experience  indicates  that  a  variety  of  such  irritants  exists. 

Imbibition  of  water  alone  is  unable  to  produce  the  changes  of 
parenchymatous  degeneration,  for  they  are  lacking  in  hydrops  or 
edema  (see  later  under  Cytolysis  and  Edema). 

As  regards  function  in  parenchymatous  degeneration,  it  is  in- 
teresting and  important  that,  as  already  pointed  out  by  Virchow, 
parenchyma  cells  may  be  irritated  to  greater  functional  activity, 
early  in  the  lesion.  Thus  liver  cells,  kidney  cells,  and  cells  of  mucous 
membranes  may  hypersecrete,  but,  as  protoplasm  undergoes  the 
profound  changes  recorded  above,  function  is  correspondingly 
depressed,  abolished  or  perverted  until  regeneration  of  normal 
protoplasmic  constitution  occurs. 


PATHOLOGICAL  CHANGES  IN  CELLS  183 

(6)  Mucoid  Degeneration.  Mucus  is  a  homogeneous,  tenacious, 
thready,  thick  mass  which  is  precipitated  by  dilute  acetic  acid 
and  dissolved  by  dilute  alkalies.  Chemically  mucus  contains  largely 
mucin,  a  glycoproteid,  that  is,  a  proteid  with  a  carbohydrate 
radicle.  In  microscopic  sections  muqus  may  be  fixed  by  the  ordi- 
nary methods.  It  stains  bluish  with  hematoxylin,  purple  with  thio- 
nin,  and  pink  to  red  with  carmine.  Normally  mucus  is  a  product 
of  epithelium  and  some  connective  tissues.  Epithelium  throws  the 
mucus  secretion  on  its  surface  where  it  forms  a  film.  Under  patho- 
logical irritations  the  secretion  of  mucus  may  be  increased  (catarrh), 
and  it  may  become  so  excessive  as  to  consume  the  secreting  cells 
in  a  mucoid  mass.  Thus  the  cell  is  transformed  into  mucus,  often 
desquamated  from  its  lining  and  lost.  This  pathological  hypersecre- 
tion  is  characteristic  in  tumor  cells  derived  from  mucous  mem- 
branes and  in  cysts.  It  is,  therefore,  frequently  found  in  glandular 
cancer  of  the  stomach  and  gut.  A  similar  condition  occurs  in  cystic 
tumors  of  the  ovary.  The  secretion  in  these  cases  resembles  mucus 
morphologically,  but  differs  in  some  respects  chemically,  princi- 
pally by  not  being  precipitated  by  acetic  acid.  It  is  spoken  of  as 
pseudomucin. 

Certain  connective  tissues  contain  considerable  mucus,  em- 
bedded as  gelatinous  ground  substance  between  stellate,  anasto- 
mosing cells.  This  is  physiological  in  the  umbilical  cord  (Wharton's 
jelly).  In  extrauterine  life  this  mucoid  connective  tissue  is  normally 
maintained  only  in  synovial  membranes.  Under  pathological  condi- 
tions, however,  connective  tissues  may  again  show  mucoid  secre- 
tion and  transformation.  Cells  revert  then  to  embryonic,  stellate, 
anastomosing  forms  and  are  embedded  in  a  gelatinous  matrix. 
This  occurs  particularly  in  connective  tissue,  tendons  and  certain 
inflammatory  growths. 

(c)  Colloid  Degeneration.  The  term  colloid  is  somewhat  loosely 
employed  and  applied.  Strictly  speaking  it  is  given  to  certain  epi- 
thelial secretions  which  are  of  uncertain  chemical  constitution,  but 
of  uniform  physical  properties.  They  are  all  homogenous,  thick, 
coherent  drops,  or  masses.  Unlike  mucus,  they  do  not  precipitate 
in  threads  and  strings  and  stain  with  acid  stains,  such  as  fuchsin  or 
eosin,  red,  with  picric  acid,  yellow;  but  not  with  hematoxylin  or 


184  GENERAL  PATHOLOGY 

other  basic  or  alkaline  dyes.  Treatment  with  acetic  acid  or  alcohol 
does  not  precipitate  colloid  as  it  does  mucus. 

Physiologically  the  best  representative  of  this  class  of  bodies  is 
the  product  of  the  thyroid  gland.  This  colloid  is  distinguished  from 
others  by  the  presence  of  an  iodine-containing  proteid.  The  ma- 
terial appears  first  as  fluid  drops  in  the  epithelial  cells.  These,  on 
being  discharged  into  the  alveolar  lumen,  fuse  to  fill  the  whole 
tubule. 

A  pathological  increase  in  this  secretion  occurs  in  diseases  of  the 
thyroid  gland,  especially  in  goiter,  in  which  the  organ  increases  in 
size  and  elements.  As  in  mucoid  degeneration,  cells  may  thus  be 
destroyed,  consumed  by  their  own  secretion.  A  similar  secretion 
occurs  in  the  anterior,  glandular  part  of  the  hypophysis  cerebri,  and 
may  also  be  increased  in  certain  pituitary  growths. 

A  colloid  material,  physically  similar,  but  chemically  quite  dif- 
ferent, is  sometimes  found  in  cystic  tumors.  In  certain  inflamma- 
tions of  the  kidney  epithelial  cells  of  the  convoluted  tubules  under- 
go a  peculiar  fusion  to  a  colloid  material  and  appear  in  the  urine 
as  so-called  waxy  casts  (so-called  on  account  of  their  appearance, 
but  not  of  the  same  material  as  the  waxy  amyloid;  see  below). 

(cQ  Hyaline  Degeneration.  Mucoid  and  colloid  degenerations 
depend  essentially  on  hyperproduction  of  cell  secretions.  In  hya- 
line and  amyloid  degenerations,  on  the  other  hand,  substances 
appear  in  and  between  cells  which  are  not  the  products  of  cell 
secretion,  but  represent  either  a  transformation  of  cell  protoplasm 
or  a  precipitation  of  foreign  material  in  tissues. 

Hyaline  degeneration  is  a  common  change.  It  consists  in  con- 
version of  cell  protoplasm  into  a  homogeneous,  glassy,  albuminoid 
material,  so  that  cell  structure  and  definition  are  lost.  It  usually 
affects  a  definite,  circumscribed  area  in  which  the  cells  fuse.  Thus, 
the  whole  wall  of  blood  vessels  may  become  hyaline,  or  connective 
tissue  or  muscle  fibrils  fuse  to  homogeneous  masses.  The  term  hya- 
line refers  principally  to  the  physical  appearance  of  such  tissues 
(in  poorly  vascularized  inflammatory  and  tumor  tissues  and,  as  a 
wear  and  tear  phenomenon,  especially  in  blood  vessels).  Hyaline 
takes  acid  stains  diffusely  and  is  occasionally  associated  with  other 
degenerative  (fatty  and  calcareous)  changes  (see  below).  It.  also 


PATHOLOGICAL  CHANGES  IN  CELLS  185 

occurs  as  the  result  of  infections  and  intoxications,  especially  in 
heart  musculature.  Muscle  fibrils  swell,  become  hemogenous 
and  fuse  in  small  or  large,  but  circumscribed,  districts  (Zenker's 
degeneration) . 

The  nature  of  hyaline  degeneration  is  not  clear.  It  is  probably 
the  result  of  protoplasmic  coagulation  with  subsequent  cell  fusion. 
Thus  structureless  homogenous  areas  are  produced. 

Similar  hyaline  solidification  or  fusion  may  be  experimentally 
obtained  by  coagulation  of  protein.  The  different  staining  affinities 
of  hyaline  surfaces — for  example,  of  connective  tissue  hyaline  to 
eosin  and  of  muscle  and  epithelial  hyaline  to  picric  acid — depend 
upon  selective  adsorption,  just  as  we  observe  it  in  coagulated  sur- 
faces of  protein.  Thus,  in  coagulated  spheres  of  egg  albumin,  the 
outer  layers  take  eosin  most  readily  and  rapidly,  the  inner  picric 
acid;  and  in  mixed  eosin  and  picric  acid  solutions,  the  picric  acid 
passes  rapidly  through  the  outer  eosin  stained  layers  towards  the 
center,  while  the  eosin  stain  remains  long  confined  to  the  periphery. 

These  phenomena  seem,  at  least,  partly,  to  depend  upon  the 
rapidity  with  which  particles  of  stains  in  solution  pass  through, 
and  attach  themselves  to  the  coagulated  proteid  particles.  But  it 
it  unknown  what  determines  this  selective  adsorption.  The  affinity 
to  basic  or  alkaline  stains  (hematoxylon)  is  also  very  weak  or 
absent  in  coagulated  proteins,  just  as  in  the  hyalines. 

A  peculiar  hyaline  material  is  to  be  observed  at  times  in  endo- 
thelial,  perivascular  tumors.  Hyaline  masses  and  bars  are  deposited 
between  groups  of  tumor  cells  and  in  vessel  walls,  which  themselves 
are,  at  least  partly,  consumed.  The  origin  of  this  hyaline  substance, 
somewhat  similar  to  amyloid  in  appearance  and  distribution,  is 
uncertain  (cell  secretion?). 

(e)  Amyloid  Degeneration.  In  this  occurs  progressive  precipita- 
tion in  tissues  of  a  thick,  clumpy,  homogeneous,  waxy  substance 
which  is  characterized  by  specific  reactions.  It  may,  therefore,  be 
regarded  as  an  entity.  The  degeneration  is  apt  to  become  diffuse 
and  extensive,  a  point  of  contrast  to  hyaline  degeneration,  which 
remains  localized.  Frequently  liver,  spleen  and  kidney  are  thus 
affected  extensively.  They  are  then  grossly  recogn  zable,  tough, 
leathery,  glassy  in  cross-sections,  or  waxy  (lardaceous)  with  oblit- 


1 86  GENERAL  PATHOLOGY 

eration  of  normal  markings.  The  volume  and  specific  gravity  of 
these  organs  is  increased.  Lesser  degrees  show  a  more  circum- 
scribed, but  unlimited  involvement  of  an  organ,  which  can  gene- 
rally be  brought  out  clearly  by  chemical  reactions.  With  iodine, 
amyloid  stains  dark  mahogany  brown,  with  methyl  violet  or  gen- 
tian violet,  red;  and  iodine  plus  I  per  cent.  H2S04,  blue  or  purple 
(for  exceptions  see  below). 

It  was  on  account  of  the  iodine-brown  reaction  that  Virchow  first 
spoke  of  it  as  amyloid — starch-like.  Later  chemical  analysis  proved 
it  to  be  a  proteid  of  rather  complex  and  not  altogether  certain  con- 
stitution. Until  quite  recently  it  was  regarded  as  a  combination  of  a 
histone-Iike  base  and  chondroitin  sulphuric  acid,  but  the  latter 
seems  to  be  only  an  occasional  admixture. 

Thus  it  happens  that  amyloid  differs  in  its  staining  reactions. 
The  proteid  part  responds  to  the  methyl  violet  or  gentian  violet 
reactions  and  is  generally  constant.  The  iodine  reaction,  however, 
is  not  always  given,  disappears  with  age  of  the  amyloid  material 
or  in  sections  of  amyloid  organs  and  seems  to  depend  upon 
other  not  yet  sufficiently  isolated  and  changeable  constituents 
of  the  amyloid  substance.  Amyloid  makes  its  first  appearance, 
like  hyaline  degeneration,  in  the  walls  of  blood  vessels  and  capil- 
laries, but  is  more  clumpy,  thicker  and  often  irregular.  Gradually 
the  coats  of  the  blood  vessels  are  completely  taken  up  and  thick- 
ened by  amyloid;  and  from  the  vessel  walls  the  material  progress- 
ively infiltrates  the  surrounding  tisue.  It  is  deposited  between  cells 
which  it  leads  to  atrophy  and  disappearance.  Thus  in  the  liver,  it 
appears  first  in  the  central  vein  and  intralobular  capillaries;  in  the 
spleen,  in  the  arterioles  of  the  Malpighian  corpuscles;  in  the  kidney 
in  the  glomeruli.  Its  advance  is  made  by  the  deposit  of  structureless, 
solid,  fusing  clumps  into  the  surrounding  tissues  which  it  gradu- 
ally replaces.  The  character  of  the  lesion  is,  therefore,  that  of  an 
infiltration  in  which  cells  are  brought  to  loss,  but  do  not  take  part. 

As  to  the  origin  of  the  amyloid  material,  nothing  very  definite  is 
known.  It  occurs  in  certain  chronic,  wasting  diseases,  especially 
when  associated  with  much  purulent  fusion  and  destruction  of 
tissues:  tuberculosis,  especially  of  joints  and  bones,  syphilis,  old 
chronic  empyema  of  pleura,  etc.  Experimentally  it  has  been  possible 


PATHOLOGICAL  CHANGES  IN  CELLS  187 

to  produce  amyloid  degeneration  in  animals  in  some  instances  of 
long-maintained  staphylococcus  infections. 

In  view  of  the  chemical  character  of  the  substance,  and  the 
manner  of  its  occurrence  and  progress,  it  is  reasonable  to  assume 
that,  in  long-continued  tissue  destructions  (and  purulent  infiltra- 
tions) foreign  proteids  are  produced,  resorbed  and  precipitated 
by  a  ferment  or  other  precipitant,  possibly  a  chondriotin  sulphuric 
acid,  in  organs  and  blood  vessels  which  are  rich  in  the  precipitant. 

Corpora  amylacea  are  peculiar  concentric,  laminated  bodies 
which  occur  in  the  central  nervous  system,  the  prostate  and  in  old 
edematous  hemorrhages,  or  inflammatory  foci,  especially  in  the 
lung.  They  give  amyloid  reaction.  Gross  has  shown  that  they  are 
due  to  a  fusion  of  degenerated  desquamated  cells  around  which,  as 
a  nucleus,  crystalline  substances  precipitate.  In  old  edematous 
and  hemorrhagic  lungs  all  stages  of  this  process  could  be  traced 
from  the  fusion  of  edematous,  desquamated  cells  with  concentric 
precipitation  of  blood  pigment  shells  (probably  a  surface  tension 
phenomenon),  to  the  gradual  deposit  of  crystalline  substances 
from  the  edematous  fluid  around  this  crystallization  center. 

II.  Fatly  Metamorphoses. — Fat  and  fat-related  substances  are 
contained,  partly  free,  visible  and  partly  in  emulsified,  invisible 
state,  in  normal  tissues  and  cells.  These  fat  contents  undergo, 
even  under  physiological  conditions,  considerable  variation:  after 
digestion,  for  example,  fat  in  the  liver  is  much  increased  and  fat 
is  plainly  visible  in  the  liver  cells.  But  permanent  extensive  fat 
content  of  cells  and  organs  becomes  pathological,  for  it  indicates 
that  they  are  either  unable  to  dispose  of  fat,  cannot  utilize  it,  or 
that  an  excessive  amount  of  fat  is  furnished  to  them.  In  one  as  in 
the  other  case  the  appearance  of  fat  represents  lessened  oxidation. 

There  exists  another  type  of  fatty  metamorphosis  in  which  fat 
is  not  brought  to  the  cells  from  outside,  but  is  released  from  cells 
by  disorganization  of  the  protoplasmic  emulsion.  This  lesion  is, 
therefore,  related  to  parenchymatous  degeneration  and,  as  has 
already  been  stated  in  this  connection,  follows  or  is  associated 
with  cloudy  swelling  of  cells. 

In  order  to  obtain  a  clear  understanding  of  both  types  of  fatty 
metamorphosis,  it  is  necessary  to  recall  the  various  fats  and  fat- 


1 88  GENERAL  PATHOLOGY 

related  substances  which  may  occur  in  the  animal  body.  These 
are: 

1.  Neutral  Fats.     Triglycerides  of  oleic,  palmitic,  and  stearic 
acids  (glycerinesters).  These  constitute  the  main  bulk  of  fat  in  fat 
depots  and  are  easily  recognizable  morphologically  in  cells  and 
intracellular  tissue.  To  this  group  must  also  be  added  the  Ca,  Na 
and  K  soaps  of  fatty  acids  which  at  times  occur  in  the  body. 

2.  Cbolesterineslers.     Cholesterin  is  a  monovalent,  simple,  un- 
saturated  secondary  alcohol,  containing  four  saturated  hydrated 
nuclei.  It  is  a  complex  terpene  (isomeric  hydrocarbon  of  the  general 
formula  CioHi6).  Cholesterin  is  a  product  of  the  animal  body,  of 
extensive  cell  distribution,  and  occurs  free  and  in  combination 
with  fatty  acids  (protagon  is  possibly  of  this  nature).  Physically 
cholesterin  and  its  esters  bear  resemblance  to  fats  (strong  light 
refraction).  They  are  soluble  in  alcohol,  ether,  and  chloroform. 
Osmic  acid  is  reduced  (black  pigmentation  of  fat)  by  oleic  acid 
compounds.  Certain  red  analin  dyes,  like  Sudan  III  and  scarlet  red, 
are  very  soluble  in  them  and  they,  therefore,  are  well  suited  for 
staining  them.  On  account  of  their  highly  light  refractive  nature, 
they  appear  optically  like  fat  droplets,  but  are  somewhat  more 
elongated  than  the  spherical  drops  of  neutral  fats  and  occasionally 
solidify  in  sections  to  crystals  (fluid  crystals). 

3.  Lipoids  or  Pbospbatides.     These  are  substances  containing  N 
and  P,  or  only  N.  Of  the  first  group,  the  lecithins  and  related 
derivatives  are  the  most  important  representatives,  of  the  second, 
the  cerebrosides  (glycosides).  Cholesterinesters  as  well  as  lipoids 
show  double  light  refraction  in  polarized  light.  They  are,  therefore, 
anisotropic. 

4.  Myelins.     When  cells  undergo  necrobiosis  or  autolytic  disin- 
tegration peculiar  fat  resembling  protoplasmic  constituents  make 
their  appearance,  which  were  recognized  by  Virchow  as  myelins. 
They  appear  in  the  form  of  larger  drops  or  refracting  clumps,  and 
produce,  if  brought  into  contact  in  the  water,  very  bizarre,  irregu- 
lar, actively  flowing  figures  and  loops.  They  differ  from  other  fats 
by  this  remarkable  behavior  and  from  cholesterin  and  lipoids  by 
lack  of  double  refraction.  They  take  origin  from  the  dissolving 
cell  emulsion  and  nucleus  after  death,  and  they  seem  not  concerned 
in  the  fat  metabolism  of  living  tissues  (Aschoff). 


PATHOLOGICAL  CHANGES  IN  CELLS  189 

The  conditions  in  which  fat  and  fat-related  substances  occur  in 
cells  may  be  divided  morphologically  into  two  groups: 

(a)  Those  in  which  the  fat  appears  in  cells  with  relatively  good 
preservation  of  cell  body  and  nucleus.  This  occurs  in  fat  infiltra- 
tion, when  fat  is  brought  to  the  cell  and  deposited  in  it.  It  may 
be  temporary,  and  purely  physiological,  and  the  fat  thus  deposited 
mainly  neutral  with  a  small  admixture  of  cholesterinesters  and 
lipoids.  Fat  infiltration  becomes  pathological  when  it  is  excessive 
and  permanent.  Thus,  in  overfeeding,  fattening  (as  in  the  pro- 
duction of  the  famous  goose  liver),  and  also  in  all  disturbances 
in  which  oxidation  ability  of  the  cell  is  diminished,  as  in  atrophy 
and  disuse,  or  from  lack  of  proper  supply  of  oxygen,  as  in  anemias, 
fat  infiltration  follows  and  may  reach  alarming  and  dangerous 
proportions.  Such  organs  are  yellow,  mottled,  ochre  colored,  friable, 
dry  and  lose  their  normal  vascular  markings. 

(6)  Those  fatty  changes  which  follow  and  go  along  with  severe 
qualitative  protoplasmic  disturbance  and  disorganization  of  cell 
emulsion  (intoxications,  severe  anemias,  cachexias).  Here  choles- 
terinesters and  lipoids,  and  later,  during  the  final  autolytic  break  up, 
myelins  become  visible.  They  appear  primarily  in  the  form  of 
minute,  highly  refracting,  fine  dust-like  granules  in  the  cell  body, 
finally  in  larger  clumps,  oblong  bodies  and  drops.  This  process, 
which,  as  was  pointed  out  before,  frequently  follows,  and  is  inti- 
mately associated  with,  parenchymatous  degeneration,  is  really 
a  fatty  disorganization  and  represents  a  severe,  internal  revolution 
in  the  cell. 

Both  lesions,  fat  infiltration  and  fat  degeneration,  or  better, 
disorganization,  may  naturally  combine,  because  disintegrating 
cells  are  deficient  in  oxidation,  and  neutral  fat,  which  is  brought 
to  these  injured  parts,  cannot  be  rapidly  disposed  of  by  these 
tissues.  This  subsequent  fat  infiltration  may,  incidentally,  be  of 
some  aid  to  injured  cells,  because  neutral  fat,  as  an  easily  combus- 
tible substance,  enables  cells  to  maintain  sufficient  oxidation  to 
survive  the  insults  of  an  irritant  (Lusk's  and  Rosenfeld's  idea  of  fat 
infiltration;  see  also  under  Glycogenic  Infiltration). 

Adipocere.  Animal  bodies  which  have  for  some  time  been 
buried  in  wet  ground  undergo  a  peculiar  waxy,  fatty  transfer- 


i9o  GENERAL  PATHOLOGY 

mation  without  putrefaction.  The  end  product  has  a  grayish, 
almost  asbestos-like  appearance  and  is  of  light  consistency  and 
specific  gravity.  It  involves  particularly  the  muscles  and  consists 
in  precipitation  of  fatty  acids  with  some  soaps  (especially  Ca  salts 
of  palmitic  and  stearic  acid).  Soluble  soaps  of  ammonium  disappear, 
so  also  does  oleic  acid  which  is  replaced  by  hydroxystearic  acid. 
This  is  characteristic  for  adipocere  (Ruttan).  Originally  it  was 
thought  that  the  muscle  protein  was  actually  converted  into  fat. 
This  idea  is  no  longer  held,  but  it  is  supposed  that  the  muscles  are 
only  replaced  by  fatty  acids  and  soaps  derived  from  the  original 
body  fat.  These  are  washed,  or  flow,  into  the  positions  of  the  muscles 
which  disintegrate,  leaving  the  fatty,  waxy  substances  behind. 
The  process  consists  probably  first  in  bacterial  splitting  of  the 
body  fat  into  glycerine  and  fatty  acids;  the  glycerine  is  removed, 
then  the  fatty  acids  form  soluble  soaps  and  diffuse  into  muscles 
and  other  organs.  Here  they  are  gradually  replaced  by  stable 
soaps  and  partially  disintegrate  to  fatty  acids.  The  oleic  acid  is 
converted  into  higher  fatty  acids  (Salkowski,  Zillner,  Gideon 
Wells).  Consequently  cadavers  become  lighter  during  adipocere 
formation. 

III.  Glycogenic  Infiltration.  Glycogen  occurs  as  a  physiological 
constitutent  in  many  cells,  especially  in  the  liver,  where  sugar  is 
normally  stored  as  glycogen,  and  in  muscles.  Its  demonstration  is 
made  difficult  by  its  extremely  rapid  conversion  into  sugar  (dex- 
trose) after  death.  Only  when  tissues  are  fixed  immediately  after 
death  in  absolute  alcohol,  which  precipitates  glycogen,  demonstra- 
tion is  possible  by  suitable  staining  methods  (after  Best).  Then 
it  can  be  seen  in  forms  of  granules  and  globules  in  and  outside  of 
cells.  An  inverse  relation  seems  to  exist  between  the  glycogen  and  fat 
contents  of  organs.  Rosenfeld  found  that  if  glycogen  is  administered 
to  animals  poisoned  with  phosphorus,  the  fat  contents  of  the  liver 
which  are  otherwise  greatly  increased  in  the  degenerated  liver 
cells,  diminish.  He  believes,  therefore,  with  Lusk,  that  glycogen  and 
fat  are  essentially  cell  fuel  and  in  cell  degeneration,  in  which  proto- 
plasm is  destroyed,  they  maintain  cell  life. 

Glycogen  is  found  in  abundance  in  growing  cells  and  in  func- 
tional activity.  Thus  in  the  premenstrual  period  cells  of  the  uterine 


PATHOLOGICAL  CHANGES  IN  CELLS  191 

mucosa,  leucocytes  and  even  the  stroma  are  rich  in  it.  The  same 
holds  true  of  decidual  cells.  The  cells  of  the  embryo  are  also  rich 
in  glycogen  and  glycogen  seems  to  be  withdrawn  from  the  maternal 
liver  to  nourish  the  fetus. 

Pathologically  glycogen  is  found  in  great  quantities  in  cells  and 
tissues  under  similar  conditions,  i.e.,  in  inflammatory  and  tumor 
growths.  Then,  there  exist  certain  obscure  diseases  of  carbohy- 
drate metabolism  in  which  glycogen  is  found  in  places  where  it 
ordinarily  is  not  seen,  as  in  the  kidney  in  the  cells  of  the  loops 
of  Henle.  The  reason  of  this  disturbed  carbohydrate  metabolism  is 
not  yet  clear. 

On  the  other  hand  glycogen  is  diminished  in  cells  and  even  lost 
in  wasting  diseases  and  local  atrophies. 

IV.  Calcareous  Infiltrations.  Our  knowledge  of  Ca  metabolism  in 
relation  to  normal  and  pathological  calcification  has  recently  been 
materially  advanced  by  the  excellent  researches  of  Hofmeister  and 
Gideon  Wells.  Ca  occurs  under  normal  conditions  in  blood  serum 
only  in  small  amounts  (about  o.oi  i  to  0.013  gm.  per  cent,  of  CaO). 
It  is  in  the  form  of  tricalcium  phosphate  and  carbonate  and  in  two 
to  four  times  the  amount  which  is  held  in  solution  by  water.  This 
increased  solution  in  the  serum  is  brought  about  by  the  colloids 
of  the  blood  and  CO2  contents,  although  the  colloids  alone  appear 
to  be  sufficient  to  keep  the  Ca  in  solution. 

Physiologically,  precipitated  Ca  occurs  only  in  bone  in  the  pro- 
portion of  85  to  90  per  cent,  of  Ca  phosphate  to  10  to  15  per  cent. 
Ca  carbonate  and  about  1 .5  per  cent,  magnesium  phosphate.  Under 
pathological  circumstances  calcification  takes  place  as  the  result 
of  Ca  precipitation  in  tissues  which  are  ordinarily  not  the  seat  of 
solid  Ca. 

Chemically  and  morphologically  the  conditions  of  physiological 
and  pathological  calcification  are  very  similar.  In  each  case  there 
is  a  homogeneous  matrix,  which  is  dead,  degenerated  or  possesses 
at  least  a  feeble  circulation.  In  this  the  Ca  is  laid  down  in  exactly 
similar  proportions  of  Ca  phosphate  to  Ca  carbonate  in  pathologi- 
cal conditions  as  they  are  found  in  normal  ossification.  Moreover, 
it  does  not  infrequently  happen  that  tissues  which  undergo  patho- 
logical calcification  are  transformed  into  osseous  tissue,  just  as 


i92  GENERAL  PATHOLOGY 

primordial  cartilage  is,  in  endochondral  ossification,  transformed 
into  bone.  In  both  instances  a  vascular  granulation  tissue  (see  under 
Granulation  Tissue)  erodes  the  calcified  parts,  the  cells  of  the  granu- 
lation tissue  become  osteoplasts  and  from  these  bone  develops. 
Even  bone  marrow  may  in  such  pathological  cases  arise  from 
lymphoid  or  connective-tissue  cells.  Thus  it  appears  that,  whether 
precipitated  under  normal  or  abnormal  conditions,  the  presence 
of  Ca  salts  exerts  a  bone-forming  influence  on  the  surrounding 
connective  tissue.  Furthermore,  decalcified  bone  which  is  implanted 
into  a  bony  defect,  does  not  lead  to  new  bone  formation,  but  is 
followed  simply  by  fibrous  changes. 

It  has  already  been  stated  that  calcification  occurs  in  homo- 
geneous, necrotic,  degenerated,  or,  at  least,  poorly  nourished  tissues 
with  slow  blood  and  lymph  circulation.  But  pathological  calcifi- 
cation occurs  with  greatest  ease  when  the  body  fluids  are  rich  in  Ca. 
Thus  diseases,  like  osteomalacia,  in  which  resorption  of  Ca  from 
bones  occurs,  are  apt  to  lead  to  extensive  calcification  in  paren- 
chymatous  organs,  such  as  the  stomach,  kidneys  and  lungs.  Virchow 
termed  this  metastatic  calcification.  Here  precipitation  of  Cat  is 
independent  of  any  local  necrotic  or  degenerative  lesions,  but 
occurs  in  organs  which  secrete  acid  and  in  which  the  tissue  fluids 
are  of  high  alkalinity  and,  therefore,  favor  Ca  deposits. 

This  mechanism  of  precipitation  can,  however,  not  be  concerned 
in  degenerative  local  calcification  in  which  the  Ca  contents  of  the 
blood  are  not  increased.  The  cause  of  this  has,  therefore,  been  a 
subject  of  much  discussion.  It  seems  certain  that  this  precipitation 
is  not  a  chemical  reaction,  for  the  amount  of  phosphoric  acid  in  the 
tissues  is  much  too  small  to  account  for  the  quantity  of  phosphate 
in  calcified  parts,  and  CO2  does  not  only  not  precipitate  Ca,  but 
keeps  it  in  solution.  The  explanation  offered  by  Klotz  and  others 
was  that  the  process  consisted  first  in  the  formation  of  fatty  soaps 
of  Ca,  formed  by  the  union  of  fatty  products  of  cell  disintegration 
with  Ca  of  the  blood.  Later  the  fatty  acid  radicle  is  replaced  by  the 
stronger  phosphoric  and  carbonic  acid  radicles,  etc.  Recent  inves- 
tigations have  not  been  able  to  substantiate  this  view  as  the  general 
mechanism  of  calcification.  Ca  soaps  have  never  been  conclusively 
demonstrated  in  calcifying  tissues  and  no  proof  of  transformation 


PATHOLOGICAL  CHANGES  IN  CELLS  193 

of  such  soaps  into  Ca  phosphate  or  carbonate  in  tissues  has  been 
forthcoming.  The  same  lack  of  convincing  evidence  exists  as  to 
the  formation  of  a  Ca  albuminate,  which  some  believed  to  be  the 
first  step  towards  calcification. 

There  is,  therefore,  little  or  no  evidence  of  the  chemical  nature 
of  calcification,  while  it  appears  that  physical  factors  play  a  great 
role.  Hyaline  substances  with  poor  circulation  are  known  to  pos- 
sess a  strong  selective  adsorption  affinity  for  Ca,  even  in  the  nor- 
mal growing  body.  This  is  apparently  similar  to  the  adsorption 
affinity  of  certain  colloids  (gelatine  disks)  towards  crystalline  sub- 
stances in  alkaline  media  and  low  CO2  contents.  Cartilage  has,  in 
a  similar  manner,  great  affinity  for  other  salts,  such  as  NaCI  or  uric 
acid.  Calcification  is,  therefore,  most  likely  a  surface  phenomenon, 
which  is  due  to  Ca  concentration  on  colloidal,  smooth  surfaces. 
This  concentration  leads  to  saturation  and  precipitation. 

The  uniform  constancy  in  the  relation  of  Ca  phosphate  to  Ca 
carbonate  depends  upon  the  relative  solubility  of  Ca  salts  in  the 
blood,  so  that  both  are  deposited  in  calcification  in  the  same 
ratio  as  they  exist  in  normal  bone. 

The  experimental  investigations  of  MacCordick  indicate  that 
Ca  salts  exist  in  tissues  during  life  in  soft  masses,  like  unset  mortar. 
Hardening  only  occurs  when  this  mass  is  acidified,  as  by  CO2 
after  the  death  of  tissues. 

Similar  to  the  process  of  calcification  is  the  incrustation  of 
necrotic  free  masses  in  cavities,  for  example,  in  the  urinary  bladder. 
This  is  not  a  phenomenon  of  crystallization,  for  the  solution  from 
which  precipitation  occurs  (urine)  is  by  no  means  saturated  with 
the  crystalline  precipitants.  It  must  be  regarded  as  a  result  of 
surface  concentration  of  the  precipitant  on  necrotic  tissue  masses. 

V.  Pigmentation  and  Pigmentary  Degenerations.  There  are  two 
sources  of  pigments  in  the  animal  body;  in  the  first  the  pigment  is 
formed  in  the  body,  in  the  second  it  is  introduced  from  outside. 
Consequently  we  may  recognize  two  groups;  the  endogenous  and 
exogenous  pigments. 

A.  Endogenous  Pigments.  These  may  again  be  divided  into  two 
classes:  (i)  the  autogenous  pigments  of  metabolic  origin;  (2) 
hemoglobin  derivatives. 

13 


i94  GENERAL  PATHOLOGY 

Pigments,  partly  physiological  in  skin,  muscle,  eye,  etc.,  may 
under  pathological  conditions  either  increase  or  appear  in  ab- 
normal situations  and  tissues. 

i.  Autogenous  Pigments.  The  chemical  constitution  of  these  is 
still  very  obscure,  but  several  types  may  be  recognized. 

(a)  Melanins  appear  as  brown  or  black  granules  in  cells  and  out- 
side of  them  and  have  their  physiological  prototype  in  the  eye, 
hair  and  skin.  Pigmented  cells  are  known  as  chromatophores.  In 
the  skin  melanins  occur  in  the  deeper  cells  of  the  rete  Malpighi, 
especially  around  the  nipple,  anus,  etc.  During  gravidity  pigmenta- 
tion increases.  A  similar  increase  may  be  observed  on  exposure  to 
the  light  rays  of  the  sun  (freckles,  bronzing).  Melanotic  pigment 
occurs  in  the  neighborhood  of  inflammations  of  the  skin,  in  moles, 
birthmarks,  and  especially  in  growths  which  take  their  origin  from 
normally  pigmented  cells,  such  as  tumors  arising  from  the  choroid 
coat  of  the  eye,  pigment  layer  of  the  suprarenal  gland  and  also 
from  pigmented  cells  of  the  skin.  A  peculiar,  first  patchy,  then 
diffuse  brown  pigmentation  of  skin  and  mucous  membranes  (tongue, 
mouth,  gums)  occurs  in  Addison's  disease,  which  is  the  result  of 
disease  of  the  suprarenal  gland  or  of  the  chromafFme  system.  This 
pigment  is  probably  due  to  a  lack  in  normal  reduction  of  cer- 
tain metabolic  products  from  absence  of  suprarenal  or  chromaf- 
fine  cell  function. 

The  origin  of  the  various  forms  of  melanins  is  uncertain, 
but  they  have  no  relation  to  hemoglobin.  It  is  not  unlikely 
that  they  owe  their  formation  to  action  of  certain  cell  ferments 
on  protein  products.  Thus,  an  oxidizing  ferment  may  change 
tyrosin  to  a  black  pigment,  and  adrenalin  may  also  through 
oxidizing  ferments  be  converted  into  a  dark  pigment.  Such 
ferments  are  known  to  exist  in  certain  mushrooms,  in  the  octopus 
and  in  pigmented  tumors. 

The  urine  of  individuals  carrying  such  tumors  may  contain 
a  substance  which,  on  exposure  to  air,  darkens  and  even  blackens. 
Cartilage  contains  at  times  a  dark-brown  pigment,  giving  rise  to 
what  is  known  as  occhronosis  (from  obxpoj  =  ochre  colored).  This 
is  also  probably  derived  by  action  of  a  ferment  on  a  protein  decom- 
position product. 


PATHOLOGICAL  CHANGES  IN  CELLS  195 

(6)  Luteins  occur  normally  as  yellow  pigments  in  fat  and  certain 
cells  of  the  ovary  which  replace  the  ruptured  Graafian  follicles. 
Pathologically  a  similar  pigmentation  is  seen  in  xanthomata  and 
lipomata  (fatty  tumors). 

(c)  Wear  and  tear  or  disintegration  pigments  are  precipitated, 
probably  from  normal  cell  constituents,  in  cells  during  atrophy 
(brown  atrophy  of  heart  muscle  fibers).  They  also  occur  in  the 
intestinal  raucosa.  They  are  of  fatty  nature,  stain  with  Sudan  III 
ancf  are,  therefore,  referred  to  as  lipochromes. 

(2)  Hemoglobin  derivatives  are  direct  descendants  from  blood 
pigment  and  occur  abundantly  in  organs  under  increased  blood  de- 
struction, blood  poisons  (hemolysis),  and  severe  progressive  anemias. 
Hemoglobin  derivatives  appear  also  as  brownish  granular  matter 
in  parenchymatous  organs  (kidney,  spleen,  liver).  It  is  to  be  seen 
in  two  forms — as  pigment  containing  iron,  hemosiderin,  and  as 
iron-free  pigment,  hematoidin.  The  presence  of  iron  is  easily  demon- 
strated by  treating  whole  fresh  organs  or  frozen  sections  with  potas- 
sium ferrocyanide  and  HCI.  Prussian  blue  is  formed.  Ammonium 
sulphide  stains  iron  containing  pigments  a  dark  black. 

Hemosiderin  occurs  in  cells,  and  through  the  action  of  cells 
which  have  taken  up  blood  pigment  by  phagocytosis.  Thus  the  liver 
cells,  Kuppfer's  cells,  the  splenic  pulp  cells  and  the  epithelial  cells 
of  the  convoluted  tubules  in  the  kidney  may  be  studded  with  it.  It 
occurs  also  in  the  endothelial  linings  of  capillaries  and  in  the  bone- 
marrow  cells.  Lymph  glands  are  also  occasionally  the  seat  of  this 
pigmentation,  when  hemosiderin  is  transported  by  the  lymph. 
Hemosiderin  may,  under  the  influence  of  putrefaction,  be  dis- 
colored to  green  iron  sulphide  by  action  of  H2S  (greenish  dis- 
coloration of  the  gut  after  death).  Hematoidin,  on  the  other  hand, 
which  is  Fe  free,  is  formed  without  intervention  of  living  cells  from 
old  hemorrhages  into  cavities  (hematoma)  and  into  necrotic  tis- 
sues. It  is  identical  with  bilirubin. 

Malaria  causes  extensive  siderosis  in  cells,  but  in  addition  a 
specific  pigment  in  endothelial  cells  which  is  Fe  free  and  a  metabolic 
product  of  the  malarial  parasite. 

Icterus  (jaundice)  depends  upon  resorption  of  bile  pigment 
from  the  liver  into  lymph  and  blood  circulation  with  consequent 


i96  GENERAL  PATHOLOGY 

bile  pigmentation  of  all  tissues,  only  the  central  nervous  system 
escapes  in  adults,  but  not  in  children  (see  below).  Bile  is  a  product 
of  the  liver  cells  and  derived  from  hemoglobin,  possibly  after  pre- 
vious preparation  by  the  spleen.  It  is  discharged  through  fine 
intralobular  bile  channels  into  larger  interlobular  ducts  and  ulti- 
mately through  hepatic  and  common  duct  into  the  intestines.  In 
the  gut  bilirubin  is  oxidized  by  bacteria  into  biliverdin  and  this 
into  hydrobiliverdin  which  is  identical  with  urobilin,  the  urinary 
pigment. 

Bile  may  be  diverted  in  its  normal  course  as  the  result  of  stagna- 
tion in  the  larger  bile  ducts  or  in  the  liver  lobules  (bile  stones,  etc.). 
This  is  known  as  obstructive  jaundice.  The  resorption  of  bile 
occurs  when  backward  pressure  is  great  enough  to  force  the  bile 
into  the  portal  zone  of  the  liver  lobules,  and  Biirker  has  shown  this 
to  follow  an  overpressure  of  20  mm.  Hg.  Resorption  does  not  occur 
from  the  interlobular  ducts  lined  by  cylindrical  epithelium,  but  in 
the  liver  lobules.  Thus  it  follows  that  occasionally  cases  of  ob- 
struction in  larger  ducts  occur  without  jaundice,  for  the  pressure 
may  never  rise  sufficiently  to  force  the  bile  into  the  peripheral 
lobular  zones.  This  may  be  due  to  an  intermittent  escape  of  bile 
(movable  obstruction;  stone  in  the  common  bile  duct;  thin  watery 
bile)  which  just  sufficiently  relieves  the  pressure  to  prevent 
jaundice,  or,  to  a  not  yet  well  understood  reflex  (?)  cessation  of 
bile  secretion.  In  cases  in  which  this  regulatory  mechanism  fails, 
the  interlobular  bile  capillaries  become  engorged  with  stagnant 
secretion,  ultimately  rupture  and  discharge  their  contents  through 
perivascular  spaces  and  blood  capillaries  into  the  general  circula- 
tion. The  liver  tissue  imbibes  the  bile  pigment  and  becomes 
necrotic.  Such  cases  are  frequently  complicated  by  an  ascending 
infection  of  the  bile  ducts  which,  of  course,  adds  to  the  mechanical 
obstruction. 

Very  difficult  of  explanation  are  cases  of  so-called  hematogenous 
jaundice  in  which  no  gross  or  coarse  interference  with  the  bile 
flow  in  or  outside  the  liver  can  be  demonstrated.  These  occur  in 
extensive  blood  destructions,  septic  fevers,  various  toxemias,  etc., 
and  are  practically  always  associated  with  marked  degeneration 
of  the  liver  parenchyma.  Some  instances  may  be  explained  by  the 


PATHOLOGICAL  CHANGES  IN  CELLS  197 

formation  of  intralobular  bile  thrombi  (coagula)  as  the  result  of 
toxic  (ferment?)  action,  which  block  the  intralobular  capillaries 
(Eppinger),  but  in  many  cases  these  are  entirely  absent. 

My  own  investigation  of  such  cases  leads  me  to  believe  that  they 
are  due  to  precipitation  of  bile  from  the  fluid  cell  state  to  solid 
form,  and  that  this  depends  upon  certain  specific  qualitative  dis- 
turbances in  the  cell  protoplasm.  In  some  of  these  cases  exists 
also  toxic  hypersecretion  of  a  thick,  viscid  bile.  The  bile  is,  there- 
fore, thrown  out  of  solution.  It  is  then  set  free  by  cell  death  or 
discharged  by  fluid  cell  currents  into  perivascular  spaces  and  blood 
capillaries.  Interesting  and  important  in  this  connection  is  the 
fact  that  the  extent  of  bile  precipitation  in,  or  jaundice  of,  the 
liver  and  general  icterus  do  not  stand  in  equal  relation,  but  often 
in  strange  inverse  ratio. 

I  have  frequently  encountered  marked  general  jaundice  with 
relatively  mild  bile  inbibition  in  the  liver  cells  and,  vice  versa, 
marked  and  extensive  bile  precipitation  in  the  liver  cells  without  any 
skin  or  organ  jaundice.  Thus,  in  a  recently  observed  case  of  portal 
cirrhosis,  jaundice  was  very  marked  in  the  otherwise  well-preserved 
liver  cells,  but  absent  elsewhere.  Bile  precipitation  in  the  liver 
cells  is,  therefore,  in  hematogenous  jaundice  only  the  first  step 
towards  general  bile  dissemination.  A  second  requisite  is  discharge 
of  the  bile  into  the  circulation  by  cell  necrosis  or  cell  currents.  Much 
discussion  has  arisen  over  the  question  whether  bile  resorption 
takes  place  by  lymph  or  blood  circulation.  There  is  as  yet  no 
unanimity  of  opinion  whether  lymph  vessels  occur  in  the  liver 
lobules  or  not.  My  own  view  is  that  perivascular  lymph  spaces 
exist  in  the  liver  lobules  and  that  these,  as  well  as  capillaries 
directly,  take  up  the  precipitated  bile  pigment. 

Bile  is  toxic  to  parenchyma  cells.  This  is  due  to  the  presence 
of  bile  acids  and  also,  as  recently  found,  to  the  pigment. 

Curious  and  obscure  is  the  jaundice  of  the  new-born  (icterus 
neonatorum).  It  occurs  soon  after  birth  and  disappears  rapidly. 
It  may  have  some  relation  to  the  sudden  nutritional  and  metabolic 
changes  and  demands  made  on  the  liver  when  the  child  assumes 
extrauterine  independence.  Possibly  also  the  abundant  hemoglobin 
destruction  with  bile  hypersecretion  which  occurs  soon  after  birth 


i98  GENERAL  PATHOLOGY 

may  have  something  to  do  with  it.  Interesting  is  that  here  the 
ganglion  cells  of  the  nervous  system  may  show  pigmentation 
which,  as  mentioned  before,  never  occurs  in  the  icterus  of  adults. 

B.  Exogenous  Pigments.  Foreign  pigments  which  are  introduced 
from  outside  may  cause  either  local  or  general  body  pigmentation. 
Thus,  picric  acid,  silver  and  lead,  the  latter  two  especially,  lead  to 
characteristic  appearances.  In  each  instance  the  metal  is  precipi- 
tated in  cells  of  skin  and  elsewhere  (kidney),  etc.  In  picric  acid  the 
skin  assumes  an  icteroid  color,  but  the  urine  remains,  of  course, 
free  (occasionally  taken  by  malingerers).  In  chronic  silver  poisoning 
(argyria,  occasionally  in  silver  washers,  etc.)  the  skin  is  of  a  peculiar 
bluish  gray,  almost  cyanotic  appearance.  In  chronic  lead  poisoning 
a  characteristic  bluish  line  appears  on  the  gums.  Carbon  particles 
are  generally  found  in  the  respiratory  tract,  in  lungs  and  bronchial 
lymph  glands  as  a  result  of  inhalation.  Sometimes  this  reaches  a 
high  degree  and  leads  to  scar  formation  (anthracosis). 

Mention  must  finally  be  made  in  this  connection  of  absence  of 
normal  pigment  under  abnormal  conditions.  This  may  be  heredi- 
tary. Albinos  are  generally  quite  pigment-free.  A  loss  of  normal 
pigmentation  also  occurs  from  inflammatory  lesions,  in  scars,  or 
in  the  peculiar  skin  lesion  of  leucoderma.  This  is  of  syphilitic 
origin  and  leads  to  the  formation  of  large,  pearly  white,  confluent 
patches  which  follow  syphilitic  skin  eruptions.  Vitiligo,  also  a 
skin  disease,  is  characterized  by  the  appearance  of  patchy,  localized 
loss  of  normal  skin  pigment.  The  skin  around  these  patches  shows 
deeper  than  normal  pigmentation.  Its  character  is  not  clear. 

3.  NECROSIS,  (from  veKpbs  =  dead  body).  We  understand  by 
the  term  "necrosis"  local  death,  and  distinguish  it  from  general  or 
somatic  death.  The  process  of  dying  in  cells  and  tissues  is  referred 
to  as  necrobiosis.  Necrosis  occurs  (i),  when  an  injury  from  a 
pathological  irritant  is  so  rapid,  severe  or  prolonged  that  adapta- 
tion to  the  changed  environment  is  not  or  is  no  longer  possible;  (2) 
as  a  result  of,  or  from,  extreme  quantitative  cell  reduction,  that  is, 
extreme  atrophy.  Such  conditions  arise  from  mechanical  reasons, 
(pressure  atrophy,  cessation  of  circulation,  edematous  inhibition) 
or  thermal  (heat  beyond  point  of  coagulation,  rays  of  certain 
lights)  or,  finally,  chemical  (inorganic  and  organic  poisons,  toxins). 


PATHOLOGICAL  CHANGES  IN  CELLS  199 

Not  all  cells  are  equally  susceptible  and  intolerant.  Ganglion 
cells  succumb  easily,  having  very  little  ability  of  adjustment; 
secretory  epithelium  and  musculature  come  next;  finally,  the  con- 
nective tissues.  The  necrobiotic  process  must  be  separated  from 
the  autolytic  changes  which  occur  in  the  cell  after  life  is  extinct. 
Necrobiosis  shows  definite,  characteristic  changes,  some  of  which 
are  related  to  cloudy  swelling  and  fatty  disorganization.  The  nu- 
cleus in  particular  undergoes  disintegration  by  karyorrhexis.  The 
following  types  of  cell  and  tissue  death  may  be  recognized. 

1.  Coagulation  Necrosis  (Weigert).     In  this  form  necrosis  takes 
place  with  coagulation  and  fusion  of  dead  and  dying  cells,  of  dead 
protoplasmic  masses  with  each  other  and  with  the  intercellular 
fluid  or  lymph.  Cell  outlines  and  cell  individuals  become  indistinct 
and  are  transformed  into  a  more  or  less  homogeneous,  structureless 
mass.  Fatty  substances,  enclosed  in  these  dead  masses,  give  occa- 
sionally a  characteristic  yellow,  butter-like  appearance.  This  is 
spoken  of  as  cheesy  necrosis.  Coagulation  necrosis  is  essentially 
the  result  of  strong  cell  toxines  and  possibly  cell  ferments.  Cheesy 
necrosis  is  characteristic  of  tuberculous  and,  in  a  lesser  degree,  of 
syphilitic  infections. 

2.  Liquefaction   or    Colliquation  Necrosis.     Here  tissues  swell, 
soften,  fuse  and  liquefy.  This  is  frequent  in  necrosis  folio  wing  simple 
obstruction  of  blood  supply  (infarcts)  in  locations  where  collateral 
circulation  does  not  exist  (end  arteries)  or  is  insufficient  (in  the 
central  nervous  system  with  preference,  also  in  burns). 

The  tendency  to  liquefy  may  distinguish  this  necrosis  from  the 
start,  or  it  may  follow  coagulation  necrosis  when  it  undergoes 
secondary  autolytic  (ferment)  softening. 

3.  Cytolytic  Necrosis.     This  type  of  necrosis  is  not  ushered  in  by 
parenchymatous   degeneration,    but  results  from  long-continued 
water  imbibition  of  cells.  It  is  seen  as  a  consequence  of  edema  (cell 
hydrops)  from  venous  congestion  and  other  causes  which  increase 
the  hydrophylic  capacity  and,  therefore,  the  water  contents  of 
cells  and  interfere  with  their  removal  (see  under  Venous  Congestion 
and  Edema). 

Here  the  cells  swell,  but  remain  distinct  in  outline  and  nucleus. 
They  do  not  fuse.  Their  protoplasm  becomes  gradually  clearer, 


200  GENERAL  PATHOLOGY 

honeycombed,  and  ultimately  simply  dissolves,  so  that  there 
remains  only  the  reticulum  or  empty  meshes.  Coagulation  and 
cell  fusion  of  protoplasmic  masses  are  entirely  absent.  The  nucleus 
may  remain  until  after  cell  solution;  then  it  simply  grows  paler  and 
fades  away.  In  the  end  tissues  appear  as  if  simply  washed  of  their 
cellular  contents.  Finally  occur  capillary  hemorrhages  into  these 
empty  spaces  (hemorrhagic  necrosis).  This  type  of  cell  necrosis  is 
common  in  the  liver  as  the  result  of  severe  and  long-continued 
chronic  venous  congestion.  It  is  generally  multiple;  certain  vascular 
poisons  with  much  edema,  like  trinitrotoluene,  may  also  lead  to 
it  (endothelial  toxines).  Similar  cell  loss  is  seen  in  hydronephrosis 
from  stagnation  of  fluid  in  the  edematous  kidney  cells  and  even  in 
the  edematous  submucosa  and  musculature  of  the  ureter. 

Certain  types  of  necrosis  are  recognized  by  special  names. 
Gangrene  is  necrosis  of  whole  parts,  organs  or  extremities  plus 
certain  external  influences.  These  are  of  two  kinds,  either  second- 
ary infection  with  putrefactive  organisms  in  the  soft,  edematous 
tissues — that  is,  wet  or  moist  gangrene,  or  simple  evaporation  of 
water,  drying  of  tissues  to  mummification — that  is,  dry  gangrene. 

In  either  case  gangrenous  parts  are  dirty,  black,  as  if  burnt, 
hence  the  name.  Soft  gangrene  is  often  of  very  disagreeable  odor 
from  putrefactive  decomposition.  Characteristic  is  the  deep,  spread- 
ing, gaseous,  moist,  bloody  gangrene  of  the  bacillus  aerogenes 
capsulatus  (see  page  87)  and  of  the  bacillus  of  malignant  edema 
(see  page  86). 

Ulcer  is  a  necrotic  loss  on  the  surface  of  an  organ,  well  localized, 
although  sometimes  involving  larger  areas,  the  base  of  which  is 
formed  by  inflammatory  tissue. 

II.    PROGRESSIVE   CHANGES 

The  so-called  progressive  changes  in  cells  are  characterized  by 
their  growth  in  size  and  number.  Increase  in  number  is  brought 
about  by  cell  division  and  this  is  either  direct  (amitosis)  or  indirect 
(mitosis,  karyokinesis).  In  my  experience  the  common  method  of 
cell  division  in  differentiated  tissues  is  normally  amitosis  and  not 
karyokinesis.  Karyokinesis  appears  more  frequently  under  difficult 
and  complicated  methods  of  division  (many  figures  and  changes 


PATHOLOGICAL  CHANGES  IN  CELLS  201 

which  have  been  described  as  mitotic  in  pathological  conditions  are 
degenerative  nuclear  phenomena).  Often  the  lack  or  scarcity  of 
mitosis  even  in  rapidly  growing  tissue  is  striking  (division  by 
amitosis).  Mitosis  is,  therefore,  not  necessarily  an  index  of  cell 
proliferation. 

None  of  the  questions  which  pertain  to  growth  and  division  of 
cells  have  so  far  been  definitely  settled  and  they  involve  the  most 
deeply  hidden  problems  of  cell  life.  The  difficulty  of  these  problems 
lies  to  a  great  extent  in  the  complications  which  are  introduced  by 
interactions  of  cell  irritants  and  cell  responses.  Any  stimulus 
which,  for  example,  excites  function  may,  by  increasing  cell  activ- 
ity, excite  to  greater  nutrition  and  thus  influence  growth  and 
ultimately  division  of  cells.  In  such  an  instance  growth  would  in 
the  end  be  the  result  of  a  functional  stimulus.  Functional,  nutritive 
and  formative  stimulations  are,  therefore,  not  infrequently  genetic- 
ally related,  or,  at  least  so  closely  associated  that  the  question  of 
their  independent  action  is  a  difficult  matter  to  solve.  For  this 
reason  the  existence  of  pure  formative  stimuli  has  been  entirely 
denied  by  some,  who  claim  that  growth  and  division  of  cells  are 
always  initiated  by  a  combination  of  environmental  circumstances. 
Ribbert,  more  especially,  attributed  much  to  changes  (release)  in 
tissue  tension  by  increased  blood  supply,  as  it  occurs  during  func- 
tional activity,  or,  in  inflammatory  cell  dislocation.  These,  in  his 
opinion,  allow  the  ever  present  latent  power  to  grow  to  become 
active.  Virchow,  on  the  other  hand,  believed  in  the  existence  of 
independent  formative  stimuli;  that  is,  stimuli  which  by  injury 
to  certain  cell  constituents  set  other  cell  activities  in  motion. 
Modern  experimental  research  has  confirmed  Virchow  and  sus- 
tained the  idea  of  formative  stimuli. 

It  is  now  well  established  that  growth  and  division  of  cells  are 
dependent  upon  release  of  certain  inhibitory  influences  which  exist 
in  the  normal  well-balanced  cell.  Such  an  upset  in  cell  balance  in 
favor  of  growth  has  been  produced  experimentally  by  Loeb  in  the 
ovum,  B.  Fischer  and  others  in  the  epithelial  cells  of  the  skin,  and 
especially  by  Reinke  in  the  cells  of  the  neural  canal  of  salamander 
larvae  and  of  the  epithelium  of  the  lens  by  exposing  them  to  weak 
lipoid  solvents.  These  cause  an  injury  to  the  cell  lipoids  which 


202  GENERAL  PATHOLOGY 

ordinarily  preserve  the  balance  of  protoplasmic  emulsion.  Reinke 
was  able  to  inhibit  this  artificial  growth  by  previous  treatment  with 
a  substance  which  he  had  extracted  from  the  lens  by  ether.  A 
degeneration  of  cell  emulsion  by  lipoid  solvents  is,  therefore,  inti- 
mately associated  with  growth  and  division  of  cells,  provided  the 
irritant  is  not  so  strong  as  to  lead  to  the  necrosis  or  complete 
disorganization  of  the  cell. 

These  important  experimental  investigations  are  borne  out  by 
general  anatomical  observations,  for  we  know  that  cell  degenera- 
tion and  cell  proliferation  are  intimately  associated  and  that  re- 
generation in  cells  and  tissues  occurs  during  and  immediately 
following  degeneration  from  injured  cells,  after  the  irritant  becomes 
attenuated  or  has  subsided.  (We  shall  see  later  that  where  an 
irritant  continues  and  tissue  architecture  or  arrangement  has  been 
destroyed,  cells  are  either  lost  entirely  or  regenerated  in  aborted 
atypical  form  and  in  pathological  arrangement;  see  under  Pro- 
ductive Inflammation  and  Regeneration). 

T.  B.  Robertson  has  made  the  additional  interesting  observation 
that  a  lipoid,  cholesterol,  accelerated  experimental  tumor  growth 
and  that  another  lipoid,  lecithin,  retards  it. 

Growth,  therefore,  is  the  result  of  an  upset  in  regulatory  cell 
balance  in  a  manner  to  increase  protoplasmic  material,  that  is,  cell 
nutrition,  at  the  expense  of  other  cell  functions  which  are,  at  least, 
temporarily  set  aside  until  the  new  protoplasmic  material  has 
arranged  and  differentiated  itself.  Consequently,  there  follows, 
first,  increase  in  size,  and  secondly,  proliferation  or  division  of  the 
cell  as  a  further  expression  of  cell  growth.  The  exact  mechanism 
by  which  growth  and  division  of  cells  occurs  is  still  very  much  in  the 
dark.  The  experiments  of  MacDougal  and  Lloyd  have  shown  that 
growth  in  certain  plant  cells  is  intimately  connected  with  proto- 
plasmic swelling  and  that  protoplasm  behaves  towards  swelling 
agents,  such  as  acids  and  alkalies,  very  much  as  gelatine  does. 
Lloyd  noted  in  pollen  the  extreme  sensitiveness  of  protoplasm  to 
low  concentrations  in  acids  and  alkalies  as  evidenced  in  swelling 
and  growth  as  compared  to  coagulation  and  syneresis  in  higher 
concentration.  The  mechanism  of  growth  in  more  complex 
plants  includes  emulsoids  which  exhibit  swellings  at  much  higher 


PATHOLOGICAL  CHANGES  IN  CELLS  203 

concentrations  of  acids  and  alkalies.  A  final  analysis  of  growth 
must,  therefore,  include  the  behavior  of  these  emulsoids. 

It  is  usually  considered  that  nuclear  division  is  essential  for 
protoplasmic  division.  That,  however,  is  not  always  the  case. 
McCIendon  has  shown  that  cytoplasm  of  cells  from  which  nuclei 
have  been  removed  is  capable,  at  least  in  low  animal  life,  of  divi- 
sion. Thus  also  in  parthenogenetic  eggs  the  division  of  the  cyto- 
plasm commences  an  hour  or  so  before  nuclear  division.  There  are, 
as  Biitschli,  Rhumbler  and  others  pointed  out,  important  changes 
in  surface  tension  in  the  dividing  cell.  Reduction  of  surface  tension 
at  the  cell  poles  causes  surface  currents  towards  the  equator  and 
constricts  the  cell  in  the  middle.  McCIendon  observed  heaping  up 
of  superficial  granules  in  the  Arbacia  egg  during  cell  division. 
Conklin  made  similar  observations  in  the  eggs  of  Crepidula.  It 
may,  therefore,  be  accepted  that  surface  tension  at  the  equator  is 
greater  than  at  the  poles  of  the  dividing  cell. 

Albrecht  and  Heilbrunn  demonstrated  an  increase  in  viscosity 
of  the  semifluid  cytoplasm  of  the  fertilized  eggs  of  the  sea  urchin. 
Chambers  showed  further  that  this  increase  in  viscosity  is  associ- 
ated with  the  appearance  of  the  aster,  a  ball  of  jelly-like 
consistency,  near  the  sperm  head.  This  astral  formation  is 
apparently  a  solidifying  process.  The  spheres  of  solidification 
grow  at  the  expense  of  all  but  possibly  a  small  peripheral  part 
of  the  fluid  egg  substance  (elongation  during  cleavage).  He 
regards  the  segmentation  process  as  essentially  a  growth  within 
the  egg  of  two  bodies  of  material  through  a  gradual  transformation 
of  the  cytoplasm. 

While  all  these  observations  bring  certain  phases  of  growth  and 
cell  division  nearer  to  our  understanding  in  their  physical  and 
colloidal  relations,  they  do  not  make  clear  the  main  issue,  namely 
the  acquisition  of  new  material  and  its  transformation  to  new 
protoplasm.  These  problems  lie  still  hidden  as  part  of  unknown 
cell  functions. 

We  can  only  say  that  certain  stimuli  change  the  surface  perme- 
ability of  cells  to  a  sufficient  extent  to  allow  entrance  of  nutritive 
material  in  larger  than  the  usual  quantity  (imbibition),  that, 
through  assimilation,  growth  results  and  that,  from  consequent 


204  GENERAL  PATHOLOGY 

changes  in  surface  tension  and  changes  in  the  colloidal  aggregate 
of  the  cytoplasm,  division  occurs. 

i.  HYPERTROPHY  AND  HYPERPLASIA.  By  hypertrophy  we 
understand  increase  in  size  of  an  organ  as  the  result  of  increase  in 
size  of  its  parenchyma  cells  with  preservation  of  the  physiological 
arrangement.  When,  in  addition,  the  number  of  cells  is  increased, 
we  refer  to  it  as  hyperplasia.  True  hypertrophy  must  be  differenti- 
ated from  enlargement  of  organs  in  which  the  quality  of  its  essential 
components  is  altered.  Thus,  excessive  fatty  infiltration  or  replace- 
ment, inflammatory  cell  infiltration  or  inflammatory  new  produc- 
tion of  foreign  tissues,  even  excessive,  unrestrained  regeneration 
of  an  organ,  may  not  be  properly  referred  to  as  hypertrophies  or 
hyperplasias.  In  them  the  enlargement  is  the  result  of  introduction 
of  elements  which  entirely  alter  the  quality  of  the  original  tissue 
and  bear  no  relation  to  the  function  of  the  organ. 

Some  hypertrophies  and  hyperplasias  stand  still  in  the  physio- 
logical category;  here  belong  the  muscle  hypertrophy  of  athletes, 
the  muscle  hypertrophy  of  the  uterus  in  pregnancy,  the  hypertrophy 
of  the  breast  in  nursing  women,  etc.  Pathological  hypertrophies 
result  from  various  causes: 

(a)  Through  mechanical  means,  that  is,  when  the  demands 
made  on  an  organ  exceed  physiological  limits,  for  example,  the 
hypertrophies  of  the  heart  in  valvular  diseases  or  when  the  periph- 
eral arterial  resistance  is  increased,  or  in  the  bladder  when  the 
flow  of  urine  is  impeded,  or  in  the  gut  above  a  stenosing  constric- 
tion, etc.  In  all  these  the  primary  causes  are  mechanical  which, 
by  excitement  of  functional,  circulatory  and  nutritive  factors,  lead 
to  growth. 

(6)  Chemical  stimuli  seem  to  play  a  role  in  the  production  of 
some  hypertrophies,  especially  in  those  connected  with  hormone 
action  of  organs  of  internal  secretion.  Thus  glandular  growths 
of  the  hypophysis  cerebri  often  lead  to  acromegaly,  that  is  hyper- 
trophies of  connective  tissues,  especially  bones,  and  giantism.  Loss 
of  the  suprarenal  gland,  on  the  other  hand,  seems  to  be  followed 
by  thymus  hypertrophy,  possibly  because  the  normal  suprarenal 
secretes  something  which  is  restraining  and  antagonistic  to  the 
thymus.  The  mechanism  of  these  hypertrophies  is  obscure.  Me- 


PATHOLOGICAL  CHANGES  IN  CELLS  205 

chanical  and  chemical  stimuli  may  combine  as  a  cause  of  hyper- 
trophy. This  is  probably  the  case  in  compensatory  hypertrophy 
when  a  part  or  organ  acts  for  another,  for  example,  hypertrophy 
of  one  kidney  after  extirpation  of  the  other.  Some  hypertrophies 
seem  to  depend  upon  hereditary  tendencies.  This  may  be  general 
or  only  affect  certain  body  parts  (hands,  feet,  etc.).  In  the  skin  it 
appears  as  congenital  skin  hypertrophy  or  ichthyosis.  To  this  cate- 
gory belong  also  certain  localized  elephantiases  of  arms,  legs  and 
feet,  often  symmetrical,  or  of  the  nails.  The  ultimate  causes  of 
such  hereditary  or  congenital  hypertrophies  are  quite  unknown. 
Histologically  the  hypertrophied  cell  is  large,  supple,  often  very 
distinct  in  differentiation  of  its  protoplasm,  but  sometimes  less 
so,  and  the  nucleus  is  large  and  rich  in  chromatin.  Coincident  with 
the  hypertrophy  of  parenchyma  cells,  especially  in  hyperplasia, 
occurs  increase  in  the  interstitial  tissues  and  in  blood  vessels. 

Finally,  it  must  be  stated  that  the  response  of  cells  to  formative 
stimuli,  and  we  include  here  the  complicated  cases  in  which  nutri- 
tive and  functional  stimuli  may  interact,  shows  great  individual 
differences.  Thus,  for  example,  not  every  muscle  is  equally  respon- 
sive to  increased  demands  by  hypertrophy.  On  the  contrary,  what 
is  stimulus  to  one  may  still  come  within  physiological  adaptation 
in  another.  This  is  commonly  expressed  by  stating  that  one  muscle 
is  stronger  than  another.  In  other  words  here  again  the  individual 
cell  specificity — whatever  it  may  be,  and  we  are  as  yet  absolutely 
ignorant  of  what  creates  and  constitutes  specificity — enters  into 
cell  function  and  lesion. 

2.  REGENERATION.  Complete  regeneration  of  tissues  to  physi- 
ological integrity  is  in  higher  animal  life  extremely  limited  and 
entirely  confined  to  localized  cell  regeneration.  Morgan  attributes 
this  largely  to  failure  of  coordinate,  concurrent  regeneration  in 
tissues  of  a  part,  some  regenerate  much  more  slowly  and  unevenly 
than  others.  Whole  organs  or  even  greater  parts  of  organs  do  not 
regenerate  and  even  where  cells  regenerate  in  an  organ  which 
has  been  extensively  injured,  regeneration  is  generally  abortive  or 
may  even  assume  pathological  character,  especially  when  injury  is 
associated  with  inflammatory  changes.  Regeneration  to  physiologi- 
cal type,  even  in  cells,  demands  that  the  architecture  of  an  organ 


206  GENERAL  PATHOLOGY 

should  not  have  been  disturbed.  New  cell  formation  which  occurs 
under  conditions  of  extensive  architectural  alteration  in  an 
organ  never  leads  to  physiologically  equal  tissue  but  is  often 
morphologically  quite  different  and  functionally  inferior  to 
the  original  (for  example,  healing  by  scar  tissue).  Generally  speak- 
ing, lower  and  more  vegetative  types  of  tissues  display  greater 
regenerative  ability  than  those  of  higher  differentiation.  Thus, 
connective  tissues  are  easily  regenerated;  nervous  tissues,  espe- 
cially ganglion  cells,  possess  hardly  any  power  of  regeneration. 
Again  surface  linings,  such  as  the  epithelial  coverings  of  the  skin, 
cornea,  and  even  the  epithelium  of  glandular  tubules  show  con- 
siderable regenerative  ability  in  replacing  defects.  Where  the 
covering  consists  of  several  layers  of  epithelium,  as  in  the  skin, 
this  is  accomplished  by  dislocation  of  superficial  cells  from  the 
surface  layers  at  the  intact  edges  of  the  loss.  They  fall,  so  to  speak, 
on  the  defect  and  then,  by  continuous  proliferation,  gradually  grow 
over  the  surface. 

Regeneration  of  Individual  Tissues.  Fibrous  connective  tissue 
regenerates  easily  by  active  proliferation  of  fibroplasts  (spindle- 
shaped  cells).  These  elongate  and  produce  collagenous  fibrils. 
They  become  thicker,  approximate  each  other  closely,  form 
wavy  bundles  and  in  maturity  lose  their  individual  cell  out- 
line. The  completed  fibrous  connective  tissue  possesses  only 
few  visible  nuclei.  It  carries  a  number  of  nutrient  blood  vessels. 
These  are  more  numerous  in  growing  and  young  connective  tissue. 
Fully  developed  connective  tissue  contains  relatively  few  blood 
vessels. 

Cartilage  regenerates  from  the  perichondrium  by  formation  of 
first  indifferent  cells  (chondroplasts).  Between  these  is  gradually 
deposited  a  homogeneous,  hyaline  ground  substance  and  the  cells 
are  thus  separated  and  encapsulated.  Besides  perichondrial  carti- 
lage formation  cartilage  may  arise  from  cartilage  cells  directly. 
Occasionally  also  periosteum  and  common  fibrous  connective 
tissue  may  form  cartilage  (see  Metaplasia).  The  formation  of 
cartilage  in  periosteum  or  fibrous  tissue  may  not  always  be  due  to 
metaplasia,  but  may  arise  from  introduced  or  misplaced  cartilage 
cells. 


PATHOLOGICAL  CHANGES  IN  CELLS  207 

Bone.  New  bone  is  not  regenerated  from  old  bone,  but  either 
from  the  periosteum  or  endostium  (bone  marrow);  occasionally 
also  from  the  perichondrium.  All  these  structures  form  at  first 
undifferentiated  osteoplastic  cells.  These  produce  a  fibrillar  ground 
substance  which  later  fuses  to  a  homogeneous  osteoid  matrix. 
Osteoplasts  are  then  confined  within  small  lacunae.  This  newly 
formed  bone  is  known  as  osteoid  tissue.  In  lamellated  bone  the 
ground  substance  arranges  itself  in  layers  or  compact  areas.  These, 
by  entrance  of  blood  vessels,  are  divided  into  spicules.  The  pres- 
ence of  calcium  salts  in  homogeneous,  feebly  nourished  tissues 
seems  to  excite  to  the  formation  of  bony  tissue  (formative  stimulus; 
see  Calcification). 

Blood  and  Lymph  Vessels.  Blood  and  lymph-vessel  formation 
is  a  necessary  requisite  of  all  extensive  cell  and  tissue  growth,  and 
they  are  most  abundant  in  young,  actively  proliferating  tissues. 
They  take  origin  by  budding  from  old  capillary  endothelial  cells. 
These  buds  are  differentiated  into  endothelial  cells.  Buds  grow 
towards  each  other,  unite  and  build  an  abundant  network.  These, 
at  first  solid  columns,  are  canalized  by  entrance  of  blood  or  lymph 
from  the  vessels  from  which  they  take  their  origin. 

Blood  is  regenerated  in  the  bone  marrow  under  normal  and  ab- 
normal conditions.  When  the  demand  is  excessive  (severe  anemia), 
other  blood-forming  organs  of  embryonic  and  fetal  life  (liver, 
spleen,  lymph  glands)  may  revert  to  hematopoietic  function  (ex- 
tramedullary  blood  formation).  In  youth  when  the  bone  marrow  is 
active  it  is  reddish  brown  (myeloid),  later  in  life  it  is  largely  re- 
placed by  fat  (yellow),  in  old  age  it  atrophies  and  is  pale  gelatinous. 
In  blood  regeneration  it  resumes  its  red  color  (erythroplastic  mar- 
row) by  active  proliferation  of  red  blood-forming  cells.  In  extra 
medullary  blood  formation  the  blood  cells  seem  to  arise,  as  in 
embryonic  life,  from  adventitial  endothelial  cells.  Leucocytes  are 
formed  in  similar  fashion.  Lymphocytes  take  their  origin  from 
lymph  adenoid  tissues  in  lymph  glands,  spleen  and  mucous  mem- 
brane; probably  not  in  the  bone  marrow. 

Muscle.  Smooth  muscle  has  very  little  regenerative  power  but 
greater  tendency  to  hypertrophy.  The  same  is  true  of  striped 
muscle  which  also  proliferates  with  difficulty.  Regeneration  occurs 


208  GENERAL  PATHOLOGY 

mostly  by  amitotic  division  and  budding.  Buds  grow  in  longitudinal 
direction  and  then  develop  striation.  Nuclei  are,  in  the  end,  placed 
peripherally. 

Nervous  Tissue.  Neuroglia  is  able  to  proliferate  abundantly 
and  form  new  tissue.  Thus  foreign  bodies,  clots,  etc.,  in  the  nervous 
systems  are  encapsulated  by  glia,  which  plays,  although  of  ecto- 
dermal  derivation,  the  same  role  in  the  nervous  system  which 
fibrous  connective  tissue  plays  in  glandular  organs.  When  new 
neuroglia  is  formed  large  dentrite  glia  cells  (so-called  spider  cells) 
make  their  appearance.  These  produce  later  fine,  delicate  neuroglia 
fibrils. 

Nerve  fibers  which  remain  still  in  contact  with  ganglion  cells 
grow  out  when  injured  or  destroyed  peripherally.  The  axis  cylinder 
grows  into  and  follows  the  path  of  the  old  one;  a  medullary  sheath 
is  formed  later. 

Ganglion  Cells.  These  cells  have  the  most  limited  regenerative 
capacity  of  any  cell,  in  fact  none  at  all,  though  they  may  divide. 
New,  fully  differentiated  ganglion  cells  to  replace  physiological 
tissue  are  not  formed.  In  some  lower,  cold-blooded  animals  (the 
frog)  this  seems  possible. 

Glandular  Organs.  Regeneration  of  parenchyma  cells  in  larger 
glandular  organs,  as  in  liver  and  kidney,  to  physiological  integrity 
and  function  occurs  only  when  the  architecture  and  arrangement  of 
the  organ  are  preserved.  Thus  when  the  tubular  structure  and  base- 
ment membrane  in  the  kidney  are  left  intact,  physiological  cell  re- 
generation is  accomplished.  In  the  liver  also,  degenerative  cell  loss 
is  usually  followed  by  complete  regeneration  as  long  as  the  lobular 
structure  and  environment  are  not  altered.  On  the  other  hand, 
when  deep-seated,  destructive  and  progressive  lesions  overtake 
these  organs  such  as  under  the  influence  of  a  chronic  irritant  and  in 
chronic  inflammations,  regeneration  to  physiological  cell  restitu- 
tion does  not  occur  and  cell  proliferation  becomes  atypical  in  cell 
type  and  arrangement.  Thus  in  the  kidney  the  newly  formed  cells 
in  the  convoluted  tubules  become  low,  flat,  endothelial  in  character. 
In  the  liver  also  nodular,  closely  packed  proliferative  areas  occur. 
These  are  phenomena  of  aborted  or  pathological  regeneration  in  a 
strange,  abnormal  environment.  They  are  frequent  in  long-con- 


PATHOLOGICAL  CHANGES  IN  CELLS  209 

tinued  inflammations,  where  inflammatory  tissues  and  products 
alter  the  whole  arrangement  and  function  of  an  organ.  Thus  these 
organs  are  gradually  transformed  to  new,  pathological  units  and 
from  these  aborted  or  pathological  regenerations  tumors  may  arise 
(see  under  Productive  Inflammation  and  Tumors). 

3.  WOUND  HEALING.  Although  not  strictly  a  regeneration  in 
the  physiological  sense,  the  process  of  wound  healing  is  conveni- 
ently considered  in  this  connection  as  a  general  example  of  replace- 
ment of  tissue  loss  or  defects  in  which  true  regeneration  cannot,  or 
only  incompletely,  be  performed. 

We  understand  by  the  term  wound  a  loss  of  continuity  in  a  tissue 
due  either  to  trauma  or  disease.  In  the  surgical  meaning  is  under- 
stood loss  of  continuity  on  surfaces  due  generally  to  trauma.  All 
processes  which  follow  this  loss  of  continuity  are  collectively 
known  as  wound  healing.  In  the  healing  of  wounds  three  phases  are 
concerned :  first,  the  wound  itself,  the  mechanical  severance  of  the 
parts;  secondly,  certain  degenerative  and  exudative  processes,  and 
thirdly,  the  actual  reestablishment  of  continuity  by  cell  prolifera- 
tion with  formation  of  a  scar  and  an  occasional  regeneration  of 
certain  functionating  parts. 

The  old  classification  of  healing  of  wounds  by  first  and  second 
intention  still  holds  good.  They  represent  only  a  matter  of  degree, 
no  essential  difference.  We  owe  our  present  knowledge  largely  to 
the  excellent  researches  of  Ziegler  and  his  pupils  and  to  Marchand. 

Healing  by  so-called  first  intention  occurs  in  rapidly  closing 
wounds  in  which  the  minimum  amount  of  damage  has  been  done, 
the  minimum  amount  of  substance  been  lost,  and  the  wound  edges 
are  in  closest  proximity  (clean,  sharp  cuts). 

Healing  by  second  intention  occurs  in  exposed  or  uncovered, 
wounds  in  which  considerable  loss  of  covering  or  substance  has 
taken  place  (irregular,  lacerated  wounds).  In  the  first  instance 
rapid  closure  of  edges  occurs,  in  the  second  healing  takes  place  by 
what  is  known  as  granulation  tissue. 

i.  Healing  by  First  Intention.  The  wound  edges  are  at  first 
closed  by  hemorrhage  from  severed  blood  vessels  and  later  by 
exuded  and  coagulated  fibrin.  At  the  edges  is  hyperemia  from 
engorgement  of  blood  vessels.  Emigration  of  polymorphonuclear 

14 


210  GENERAL  PATHOLOGY 

leucocytes  and  lymphocytes  with  fibrin  occurs  within  an  hour 
into  the  defect  from  the  capillaries  of  the  edges.  This  exudation  and 
emigration  continues  during  the  first  twenty-four  hours.  Large 
wandering  cells  (phagocytes)  partly  accomplish  the  resorption  of 
the  hemorrhage  and  fibrin. 

At  the  end  of  the  first  day  the  formation  of  new  tissue  com- 
mences. It  consists  of  proliferation  of  capillary  endothelial  cells 
and  of  connective  tissue  cells  which  grow  into  the  gap;  it  is  abun- 
dant at  the  end  of  the  second  day.  These  cells  grow  from  the  edges 
towards  each  other,  unite,  and  thus  close  the  defect  by  a  young 
vascular  connective  tissue.  Later  the  connective  tissue  cells  form 
fibrils  and  mature  to  scar  tissue  which  at  first  is  still  vascular,  red ; 
later  becomes  pale  and  firm.  Finally  the  surface  of  the  scar  is 
covered  by  epithelium  which  is  derived  from  the  wound  edges. 
The  upper  layers  of  the  adjoining  epithelium  are  dislocated, 
descend  upon  the  scar  and,  by  proliferation,  cover  it  and  join  the 
epithelial  surfaces.  Papillae  are  not  formed.  Clean,  even  extensive 
incisions,  like  surgical  wounds,  are  thus  fully  healed  in  two  or 
three  weeks.  Elastic  fibers  appear  later,  in  from  four  to  six  weeks. 
They  also  enter  from  the  edges  of  the  wound  and  increase  up  to  the 
fifth  and  sixth  week.  Similar  are  the  conditions  in  healing  of  a 
wound  under  protection  of  a  scab.  This  is  a  dried  superficial 
hemorrhage  with  exudate;  below  it  granulations  form.  The  same 
principles  apply  to  healing  of  superficial  burns. 

2.  Healing  by  Second  Intention  or  by  Granulation.  This  occurs 
when  the  wound  edges  cannot  unite  or  close  by  hemorrhage  or 
exudate,  in  other  words,  in  gaping  defects.  Here  follows  after  the 
primary  hemorrhage  has  ceased,  hyperemia  (congestion)  and 
edema  (serous  swelling)  of  the  wound  edges  and  wound  base. 
This  swelling  is  increased  by  accumulation  of  wandering  cells  (large 
lymphocytes  and  polymorphonuclear  leucocytes)  with  a  yellowish 
exudate  rich  in  albumin.  This  is  known  as  wound  secretion.  It 
spreads  over  the  whole  defect  and,  by  coagulating,  forms  a  fibrin- 
ous,  opaque,  protecting  covering.  In  this  wound  secretion  there 
appear  early  long,  slender  endothelial  cells  with  delicate  fibrillar 
processes.  They  unite  and  grow  in  double  rows  of  anastomosing 
columns  throughout  the  wound  secretion.  These  new  endothelial 


PATHOLOGICAL  CHANGES  IN  CELLS  211 

cells  arise  by  budding  from  the  endothelium  of  old  capillaries  in 
the  wound  edges,  and  remain  connected  with  them.  Consequently, 
blood  from  the  old  capillaries  gradually  forces  its  way  between 
the  new  double  rows  of  endothelial  cells  in  the  wound  surface. 
The  vis-a-tergo  of  the  blood  is  probably  of  importance  in  the 
formation  of  the  new  capillary  network.  Moreover,  the  endothelial 
proliferation  remains  limited  in  normal,  healthy  granulation  tissue, 
as  there  is  no  abnormal  and  continued  irritant.  (This  in  contrast  to 
infective  granulomata.  See  under  Tubercle  Formation.) 

This  vascularization  of  the  wound  edges  and  wound  surface  is, 
in  a  short  time,  accompanied  by  the  appearance  of  fibroplasts, 
entering  from  the  wound  edges.  At  first  round  or  oval,  they  rapidly 
assume  spindle  shape  and  enlarge  to  long  cells  with  fine,  delicate 
fibrillar  processes.  The  number  of  exuded  cells,  such  as  leucocytes, 
large  mononuclear  phagocytes,  plasma  cells,  now  steadily  decreases. 
In  about  forty-eight  hours  and  later,  in  uncomplicated  cases,  the 
wound  edges  are  seen  to  be  covered  by  a  reddish  coating  which  is 
made  up  of  proliferating  capillary  endothelial  cells  and  young 
fibroplasts. 

After  several  days  the  whole  wound  surface  assumes  a  fleshy, 
granular  appearance  (granulation  tissues).  The  granules  correspond 
to  projecting,  straight  blood  vessels,  surrounded  by  a  mantle  of 
embryonic  connective  tissue  cells  and  wandering  cells.  The  wound 
secretion  assumes  now  a  more  grayish,  less  and  less  hemorrhagic 
appearance.  The  growth  of  granulation  tissue  is  continued  until 
the  whole  extent  and  depth  of  the  defect  is  filled  by  it.  It  gradually 
matures  to  scar  tissue,  that  is,  more  and  more  spindle  cells  develop 
and  these,  as  they  mature,  produce  connective  tissue  fibrils  in  in- 
creasing abundance.  Thus  a  fine  fibrillar,  wavy  connective  tissue 
fills  the  gap.  It  is  at  first  still  red,  vascular,  then  as  it  matures,  more 
and  more  fibrous  (collagenous),  avascular,  firm,  pale  and,  of  course, 
less  and  less  cellular.  New  epithelium  which  covers  the  scar  is 
derived  from  that  of  the  edges  as  described  above  under  healing 
by  first  intention.  It  completes  the  final  closure  of  the  defect.  New 
epidermal  covering  may  also  be  derived  from  remaining  parts  of 
hair  follicles  or  glands.  Hair,  skin  glands,  and  pigment  are  not  re- 
generated, so  that  a  skin  scar  is  normally  plainly  visible  and  pale. 


212  GENERAL  PATHOLOGY 

Papillary  bodies  are  not  reformed,  but  epithelial  projections  and 
irregularities  in  the  thickness  of  the  lining  epidermis  may  be 
noted. 

As  the  connective  tissue  fibers  increase  and  thicken  and  are  more 
closely  packed,  the  scar  toughens,  retracts  and  contracts  especially 
when  elastic  fibers  become  abundant. 

Healing  by  granulation  does  not  only  occur  in  skin  wounds,  but 
in  every  loss  of  tissues  which  cannot  be  physiologically  regenerated. 
For  example,  in  defects  or  ulcers  of  mucous  membranes.  Here  it 
proceeds  in  exactly  similar  fashion  to  scar  tissue  formation  as  else- 
where. The  scar  is  finally  covered  by  the  lining  epithelium  from  the 
edges  of  the  mucous  membrane.  This  may  form  crypt-like  depres- 
sions in  the  scar,  but  no  new  glands.  Muscle  tissue  of  mucous  mem- 
branes is  not  regenerated,  but  heals  through  granulation  to  scar 
tissue  only.  The  same  is  true  in  healing  of  wounds  or  defects  (ab- 
scesses) in  parenchymatous  organs. 

Foreign  bodies  or  exudates  in  tissues  or  on  the  surface  of  an  or- 
gan which,  from  one  or  the  other  reason,  cannot  be  resorbed  are 
either  encapsulated  or  gradually  replaced  by  granulation  tissue. 
Foreign  bodies,  when  compact  (bullets)  are  thus  fixed  and  localized 
by  connective  tissue.  Soft  foreign  particles  (sponge)  are  gradually 
permeated  and  often  resorbed  and  broken  up  by  granulation  tissue. 
Multinucleated  giant  cells  are  here  conspicuous  phagocytes.  These 
are  derived  mostly  from  connective  tissue  and  endothelial  cells 
and  possibly  epithelial  cells  by  fusion  of  young  cells,  or  cell  over- 
growth with  nuclear  division  in  which  protoplasm  fails  to  divide. 
These  giant  cells  approach  and  attach  themselves  to  foreign  mate- 
rial, break  into  it,  take  it  up  and  digest  it  (sutures,  cotton,  sponge 
particles). 

When  an  exudate  on  a  surface  of  an  organ  (such  as  a  serous 
membrane)  or  in  lumina  (as  in  alveoli  of  lung)  is  not  resorbed,  it  is 
organized  in  similar  fashion,  that  is,  from  the  adjoining  or  under- 
lying walls  granulation  tissue  grows  into  the  exudate,  resorbs  and 
replaces  it.  As  this  occurs  from  either  side  of  the  lumen,  this  is 
naturally  finally  obliterated  (permanent  adhesion  of  the  surfaces) . 

Blood  coagulation  in  vessels  during  life  (thrombus)  leads  fre- 
quently to  a  similar  so-called  organization  (see  under  Thrombosis). 


PATHOLOGICAL  CHANGES  IN  CELLS  213 

Destruction  and  loss  of  nervous  parenchyma  (brain,  cord)   is 
generally  replaced  by  new  growth  of  neuroglia. 

4.  METAPLASIA  (juero:  =  after,  ir\d<rffei,v  =  to  form).     Metaplasia 
is  intimately  associated  with  regeneration,  new  formation  of  cells 
and  tissues  and  is  of  special  importance  in  tumor  growth  (see  later). 
It  consists  of  transformation  of  one  kind  of  a  tissue  into  another  of 
close  embryogenetic  relation.  This  transformation  is,  in  true  meta- 
plasia, morphological  as  well  as  functional.  It  must  be  distinguished 
from  differentiation  of  cells.  Differentiation  is  possible  only  in  em-, 
bryonic  or  young,  undeveloped  cells;  but  metaplasia  implies  that  a  I 
tissue  has  already  arrived  at  its  normal  differentiation  and  then,/ 
through  environmental  influences,  once  more  changes  its  character. 

Thus,  metaplasia  must  also  be  distinguished  from  lack  or 
failure  in  development  when  cells  or  whole  tissues  persist  in  a 
certain  stage  of  embryonic  formation.  This  is  inhibition  of  differ- 
entiation, not  metaplasia.  Ciliated  epithelium  may  be  found  in 
the  esophagus  as  a  persistence  of  embryonic  stages  in  its  epithelial 
covering.  Finally  metaplasia  must  not  be  identified  with  embryonic 
misplacements,  often  from  neighboring  parts.  Thus  islands  of 
gastric  mucosa  may  at  times  be  found  in  the  esophagus,  or  pan- 
creatic tissue  in  the  gut,  etc.  These  are  aberrant  rests,  not  meta- 
plastic  new  formation.  Metaplasia  is,  as  said  above,  due  to  altera- 
tions in  environment  under  which  tissues  live.  Particularly  potent 
are  here  functional  influences  of  mechanical  and  chemical  nature. 
Ectopia  of  the  bladder,  for  example,  leads  to  epidermization  on 
the  surface  while  the  glandular  projections  towards  the  interior 
contain  cylindrical  and  goblet  cells.  Thus  also  fibrous  tissues  may 
under  the  influence  of  lessened  nutrition,  pressure  and  especially 
by  the  presence  of  calcium  precipitation,  turn  into  bone. 

True  metaplasia  occurs  only  within  certain  related  limits. 
Epithelial  kinds  are  interchangeable,  connective  tissues  equally  so. 
These  changes  are,  so  to  speak,  repetitions  of  embryonic  processes. 
Thus  in  the  esophagus  metaplasia  to  cylindrical,  ciliated,  poly- 
gonal epithelium  may  be  formed  out  of  squamous  epithelium,  or, 
in  the  prostate  squamous  epithelium  from  glandular  epithelium. 
Again  connective  tissue  may  become  mucoid  or  cartilage  or  bone, 
or  vice  versa.  Metaplasia  rarely  occurs  in  the  old  cells  of  a  tissue, 


214  GENERAL  PATHOLOGY 

(as,  for  example,  osseous  matrix  from  connective  tissue  fibrils 
and  bone  cells  from  connective  tissue  cells  [direct  metaplasia]) 
but  more  frequently  from  a  new  offspring  of  undifferentiated  cells 
which,  by  the  altered  environment,  deviate  from  their  normal 
course  of  development.  Such  environmental  influences  are  found  in 
regenerative  attempts  under  chronic  or  specific  inflammations 
when  architecture  and  tissue  arrangement  are  profoundly  altered 
and  new  foreign  cell  types  are  introduced.  Similar  altered  tissue 
conditions  exist  in  tumors  and  thus  tumors  of  squamous  epithelium 
may,  for  example,  arise  from  glandular  epithelium  (gall  bladder, 
uterus,  prostate)  or  tumors  of  bone  cells  or  cartilage  from  fibrous 
connective  tissue,  or  growths  of  connective  tissue  from  bone  or 
cartilage,  etc.  Endothelial  cells  standing  histologically  and  embry- 
onically  between  epithelium  and  connective  tissue  may  sometimes 
form  a  tissue  resembling  one,  sometimes  another. 

From  this  true  metaplasia  must  be  distinguished  pseudometa- 
plasia  or  false  metaplasia.  This  involves  change  in  form  alone 
without  altering  the  biological  character  and  is  best  referred  to  as 
histological  accommodation  to  a  particular  locality  or  exposure. 
Thus,  connective-tissue  cells  on  exposed  surfaces  of  serous  mem- 
branes or  on  other  unprotected  surfaces  may  sometimes  take  on  a 
form  resembling  epithelium  or  endothelium,  and  epithelial  cells  in 
lymph  channels  may  assume  spindle  shape.  But  they  still  continue 
to  be  connective  tissue  or  epithelium  and  easily  revert  to  their 
previous  form.  This  reversion  does  not  occur  in  true  metaplasia. 

Finally  we  must  exclude  from  metaplasia  replacement  of  a  cell 
type  by  invasion  from  a  neighboring  tissue.  When,  for  example,  in 
chronic  inflammations  of  the  middle  ear  squamous  epithelium  of 
the  external  ear  grows  through  a  defect  in  the  drum  into  the  tym- 
panic cavity  and  replaces  its  epithelium,  or  squamous  epithelium 
of  the  esophagus  extends  to  the  mucous  membrane  of  the  stomach, 
we  are  plainly  not  dealing  with  metaphasia. 

5.  TRANSPLANTATION.  The  transplantation  of  tissues  and 
whole  organs  from  one  person  to  another  and  from  higher  animals 
to  man,  in  order  to  substitute  for  defects  or  to  replace  lost  or  di- 
seased organs,  has  been  frequently  attempted  by  surgeons  and  been 
a  favorite  matter  for  conversation  by  the  laity  and  in  the  daily 


PATHOLOGICAL  CHANGES  IN  CELLS  215 

press.  Consequently  it  cannot  be  wondered  at  that,  as  in  the  con- 
sideration of  heredity,  much  unscientific  evidence  has  been  pro- 
duced and  many  preposterous  results  have  been  claimed.  The 
whole  subject  of  tissue  and  organ  transplantation  has  been  ex- 
cellently covered  in  detail  by  the  researches  of  Borst,  who  presented 
his  results  and  those  of  other  trustworthy  workers  (very  extensive 
bibliography)  before  the  pathological  section  of  the  International 
Medical  Congress  in  London  in  1913.  His  chief  results  together 
with  observations  by  others  are  given  below. 

By  transplantation  we  understand  dislocation  of  a  tissue  or 
organ  from  its  normal  connections  and  grafting  it  upon  another 
location  of  the  same  or  another  individual.  A  successful  or  true 
transplant  is  one  in  which  the  graft  not  only  mechanically  heals 
to  the  new  tissue  and  lives  in  its  new  environment,  but  assumes 
organic  and  functional  relations  to  its  new  surroundings.  This  is 
possible  only  when  the  new  environment  is  not  too  foreign,  and 
when  the  bio-relations  of  the  transplant  to  the  host  are  very  inti- 
mate. Thus,  epidermis  takes  best  on  an  epidermal  soil,  ovaries  are 
more  apt  to  implant  within  the  peritoneum,  muscle  in  muscle, 
bone  in  bone.  The  lower  the  host  and  the  transplant  stand  in  the 
animal  scale,  the  greater  the  possibility  of  transplantation.  Cold- 
blooded animals  are,  therefore,  more  successful  in  accepting  trans- 
plants than  warm-blooded  animals,  especially  mammals. 

The  same  applies  to  cell  differentiation  in  relation  to  host  and 
transplant.  Embryonic  structures  are  better  suited  for  transplants 
and  into  young,  growing  organisms  than  fully  differentiated  parts 
into  mature  organisms.  Thus  in  young  germs  of  frogs  and  tridon 
the  optic  vesicle  will  develop  not  only  in  its  normal  situation,  but 
will  form  a  lens  after  dislocation  of  the  ectoderm  to  an  abnormal 
location,  or  a  lens  is  produced  by  transplantation  of  ectoderm  to 
the  normal  location  of  the  optic  cup  (Lewis,  Spemann).  Transplan- 
tation of  whole  embryos  (all  three  blastoderm  layers)  into  perito- 
neum, cutis,  etc.,  is  followed  by  some  growth  and  differentiation, 
but  ultimately  all  such  transplants  go  to  pieces. 

Transplantation  is  either  autoplastic,  that  is  parts  of  an  animal 
into  the  same  animal;  or  homoio-isoplastic,  that  is,  parts  of  an 
animal  into  another  animal  of  the  same  species;  finally,  hetero- 


216  GENERAL  PATHOLOGY 

plastic,  parts  of  an  animal  into  another  animal  of  different  species. 
Of  these  only  autoplastic  transplantation  is  generally  success- 
ful, true  homoiotransplantation  and  heterotransplantation  never 
succeed.  Under  the  latter  conditions  preservation  of  the  transplant 
is  impossible.  It  may,  therefore,  be  said  that  the  success  of  a  trans- 
plant is  proportionate  to  the  bio-relations  of  tissues  and  host. 

Fully  successful  is  only  autoplastic  transplantation.  Homoiotrans- 
plantations  generally  undergo  eventual  atrophy.  Some  succumb 
slower  than  others;  they  have  for  that  reason  at  times  been  mis- 
interpreted as  "takes."  Even  when  two  animals  have  been  united 
in  parabiosis  (union  by  vascular  anastomosis)  in  order  to  identify 
their  circulation  and  nutrition,  the  results  of  transplantation  have 
not  been  improved  (formation  of  hemolysis  and  other  cell  lysins, 
etc.). 

Some  evidence  exists  that  grafting  has  greater  chance  of  success 
amongst  blood  relations.  The  success  of  a  graft  even  in  autoplastic 
transplantation  is  said  by  some  to  be  improved  by  immediate  de- 
mands on  its  functional  activity,  others  deny  this.  For  example, 
thyroid  transplants  heal  quicker  after  previous  thyroidectomy; 
muscle  on  electric  stimulation;  or  ovaries  transplanted  during  em- 
bryonic or  sexually  active  phases  into  the  peritoneum  assume  nor- 
mal structure  and  functions.  In  older  animals  such  an  operation  is 
followed  by  ovarian  disintegration  and  resorption. 

The  values  of  homoioplastic  or  isoplastic  transplants  have  never 
been  anything  else  but  mechanical,  forming  bridges  or  a  scaffold 
for  regeneration  of  the  host's  own  parts.  Thus  in  transplantation 
of  bones  and  joints  from  one  individual  to  another,  gradual  sub- 
stitution of  the  plant  by  new  osseous  and  cartilaginous  tissue  of 
the  host  occurs.  It  is  possible  that  this  takes  origin  to  only  a  very 
small  extent  from  the  adherent  periosteum  of  the  plant.  The  largest 
replacement,  however,  is  always  from  the  adjoining  parts  of  the 
host.  The  transplanted  cartilage  is  also  seen  to  atrophy  and  new 
cartilage  is  formed  as  is  new  bone.  The  marrow  disintegrates  and 
is  entirely  resorbed. 

In  blood  vessels  only  autoplastic  transplantation  is  successful. 
Isoplastic  plants  atrophy  and  are  lost  in  about  two  and  a  half 
months.  They  are  gradually  replaced  by  the  tissues  of  the  host 


PATHOLOGICAL  CHANGES  IN  CELLS  217 

which  use  the  plant  as  a  bridge  to  unite  upon.  The  host's  intima 
grows  over  the  sutures  in  about  nineteen  days,  the  media  is 
not  regenerated,  but  disintegrates  and  is  replaced  by  a  cicatrix. 

Whole  glands  take  either  poorly  or  not  at  all.  Here  again,  success 
is  possible  only  in  autotransplants  (thyroid,  mamma,  ovary,  thy- 
mus,  etc.).  Even  in  autoplastic  transfers  central  necroses  may  occur, 
for  example,  in  the  ovary  after  attachment  to  the  peritoneal  serosa. 
These  necroses  are  not  regenerated,  but  healed  by  scar  tissue  only. 
New  follicles  no  longer  form  and  atypical  proliferation  in  the 
germinal  epithelium  has  been  observed.  The  testicle  atrophies  and 
is  lost,  the  epididymis  remains  somewhat  longer.  If  the  testicle  is 
left  united  to  its  stalk  of  vessels  and  nerves  and  attached  under  the 
abdominal  skin,  it  may  heal  to  the  new  location,  but  soon  follow 
disturbances  of  spermatogenesis.  Later  testicle  and  epididymis 
atrophy  and  a  cyst  remains  which  is  derived  from  the  vas  deferens. 

Liver  and  kidneys  are  entirely  unsuccessful  transplants,  also 
nervous  tissue  and  brain. 

Results  of  tissue  and  organ  transplantation  are,  therefore,  inti- 
mately associated  with  generic  and  individual  biological  peculiari- 
ties. These  are  specific  even  in  members  of  the  same  family.  In 
other  words,  the  investigation  of  transplantation  has  disclosed  once 
more  the  increasing  importance  in  the  animal  scale  of  individual 
specificity.  Interesting  in  this  connection  is  certain  other  corro- 
borative evidence.  Parabiosis  of  young  rats,  followed  by  extirpa- 
tion of  kidneys  in  one  partner,  leads  to  compensatory  hypertrophy 
of  the  kidneys  in  the  other,  but  the  partner  dies  of  cachexia  with 
heart  hypertrophy  as  in  nephritis.  So  also,  active  immunization 
of  one  partner,  living  in  parabiosis  with  another,  leads  only  to 
passive  immunization  in  the  other. 

We  stand  here  again  before  the  problem  of  specificity  and 
quality  which,  as  we  have  seen,  is  not  only  racial,  but  individual. 


CHAPTER  III 

PATHOLOGICAL  CHANGES  IN  LOCAL 
CELL  RELATIONS 

THE  pathological  processes  which  we  have  so  far  considered  were 
confined  to  nutritive  disturbances  in  cells  as  they  were  originally 
laid  down  in  physiological  tissues  and  organs.  Their  position, 
continuity  or  connection  with  each  other  were  not  altered.  A 
local  and  limited  loss  in  cell  continuity,  which  is  closed  and  re- 
placed by  granulation  tissue  and  a  scar  may  occur  as  the  result  of 
cell  destruction  (necrosis)  and  loss.  But  this  is  a  local  consequence, 
not  a  part  of  the  nutritive  disturbance  and  does  not  alter  the 
constitution  of  the  remaining  parts.  In  the  processes  which  we  now 
approach,  the  distinguishing  features  are  separation  and  disloca- 
tion of  normal  tissues  and  the,  either  temporary  or  permanent, 
introduction  of  new  cells  which  may  proceed  to  formation  of  new 
tissues.  Nutritive  changes  are  also  to  be  noted,  but  the  essential 
element  is  an  either  temporary  or  permanent  alteration  in  tissue 
and  organ  construction. 

This  group  of  processes  is  represented  by  inflammation  and 
tumors. 

I.    INFLAMMATION 

Of  all  pathological  processes  inflammation  is  perhaps  the  most 
important.  The  statement  is  made  with  some  justification  that  he 
who  has  a  clear  conception  of  inflammation  knows  pathology. 
In  no  other  field  is  a  knowledge  of  the  historic  development  of  our 
ideas  of  greater  necessity  for  an  appreciation  of  modern  views 
than  in  the  study  of  inflammation.  As  in  most  pathological  con- 
ceptions, the  idea  of  inflammation  rests  primarily  upon  subjective 
symptoms  and  evidence. 

Inflammare  means  to  burn,  and  since  olden  times  this,  the  ca/or, 
was  regarded  as  one  of  the  cardinal  signs  of  inflammation.  With 
it  went  reddening,  rubor;  swelling,  tumor;  and  pain  dolor.  Later, 
impaired  function,  functio  laesa,  was  added. 

218 


CHANGES  IN  LOCAL  CELL  RELATIONS          219 

Thus  the  early  conception  of  inflammation  centered  around 
vascular  phenomena  and  up  to  the  early  nineteenth  century, 
when  closer  anatomical  inspection  and  the  microscope  were  first 
applied  to  finer  tissue  changes,  these  phenomena  held  the  focus 
of  attention.  The  definition  of  Vogel,  for  example,  expressed  it  in 
somewhat  the  manner  of  a  formula;  inflammation  =  capillary 
hyperemia  +  hydrops  fibrinosus  (fibrinous  fluid  outside  of  the 
blood  vessels).  The  important  turning  point  came  with  Virchow. 
In  1852  he  published  in  the  fourth  volume  of  his  Archives  a  now 
celebrated  and  still  important  article  which  in  ingenuity,  boldness 
and  greatness  of  ideas  stands  as  one  of  the  classics  in  science  and 
to-day  still  is  for  the  reader  a  gold  mine  of  information  and  inspira- 
tion. It  should  be  read  by  every  student  of  medicine.  It  is  interest- 
ing to  note  in  it  Virchow's  thorough  knowledge  and  appreciation 
of  contemporary  English  literature.  The  title  of  this  paper  is 
"On  parenchymatous  inflammation"  (Uber  parenchymatose 
Entziindung).  He  was  the  first  to  use  this  term  which  has  become 
common  property.  In  this  publication  Virchow  laid  the  corner  stone 
for  all  future  ideas  about  parenchymatous  inflammation,  although 
his  original  views  on  the  genesis  of  parenchymatous  inflammation 
have  gradually  been  modified  or  altered. 

Virchow's  studies,  made  largely  in  the  inflammations  of  the 
kidney,  led  him  to  the  conclusion  that  the  so-called  exudate  (blood 
fluid  and  cells  outside  of  vessels)  was  not  the  essential  element  of  in- 
flammation, but  that  the  parenchymatous  degeneration,  that  is,  the 
cloudy  swelling  of  the  parenchyma  cells  was.  He  was  led  to  believe 
that  the  inflammatory  irritant  stimulates  cells  to  greater  function1 
and,  therefore,  greater  nutrition.  Thus  excessive  nutrient  fluid 
is  attracted  and  consumed  by  the  cells.  Consequently  they  enlarge, 
appear  swollen  and  the  albuminous  granules  in  the  cytoplasm  are 
increased.  Here,  as  in  parenchymatous  degeneration,  overnutrition 
leads  to  cell  injury.  The  cell  cannot  dispose  of  the  excessive  nutri- 
ent material,  degenerates,  becomes  fatty  and  may  entirely  disin- 
tegrate. The  fluid  exudate  is,  in  Virchow's  opinion,  only  excessive 

1  It  is  interesting  that  modern  experimental  medicine  has,  in  a  way,  revived 
and  confirmed  this  view:  notably  in  early  kidney  inflammations  epithelial 
cells  may  hyperfunctionate. 


220  GENERAL  PATHOLOGY 

nutrient  material  demanded  by  abnormally  irritated  cells.  In 
some  inflammations  all  of  this  material  is  imbibed  by  cells,  so  that 
free  fibrin  is  not  visible,  in  others,  however,  the  nutrient  fluid  is  so 
great  that  it  appears  free  and  coagulates  outside  of  cells.  Virchow, 
therefore,  concludes  his  memorable  work  with  these  significant 
words :  "  I  vindicate  above  everything  the  degenerative  character 
of  inflammation  and  although  I  regard  it  as  increased  nutritive 
phenomenon,  I  do  not  see  in  it  an  evidence  of  increased  strength, 
but  an  expression  of  its  diminution." 

Guided  by  these  considerations,  Virchow  was  the  first  to  dis- 
tinguish between  three  types  of  inflammation  for  which  he  created 
the  following  terms,  which  are  still  employed  to-day,  although  in  a 
different  sense  from  the  one  Virchow  gave  them : 

1.  Catarrhal.  Here  cells  become  granular,  opaque  and  desqua- 
mate. 

2.  Croupous.  Cells  show  essentially  the  same  change,  but  become 
mixed  with  a  coagulated  fibrinous  exudate. 

3.  True  parenchymatous  inflammation.  This  is  the  most  intense 
and  consists  of  granular  disintegration  of  cells  with  formation  of  a 
soft  detritus. 

According  to  Virchow  an  essential  difference  between  paren- 
chymatous degeneration  and  inflammation  does  not  exist,  only  one 
of  degree.  The  degeneration  of  parenchyma  cells  is  essential  and 
characteristic  to  both,  but  in  inflammation  may  be  added  free,  or 
coagulated  extracellular,  nutrient  material  (exudate). 

The  second  important  step  in  the  formation  of  our  modern  con- 
ception of  inflammation  was  made  by  Cohnheim  in  his  celebrated 
observations  and  conclusions  on  the  emigration  of  leucocytes  from 
the  blood  vessels  into  inflamed  parts  and  the  demonstration  of 
the  identity  of  leucocytes  and  pus  cells.  He  found  that  when  an 
inflammatory  irritant  is  applied  to  a  vascular  tissue  very  striking 
vascular  changes  ensue.  First  is  seen  a  temporary  rapid  contraction 
then  a  dilatation  of  vessels  with  slowing  of  the  blood  current.  This 
is  rapidly  followed  by  accumulation  of  leucocytes  to  the  walls  of 
veins  and  capillaries,  after  which  they  emigrate  into  the  fixed  tis- 
sues, floating  in  exuded  fluid.  At  the  same  time  red  cells  may  in 
varying  number  pass  out  with  leucocytes  (see  below). 


CHANGES  IN  LOCAL  CELL  RELATIONS          221 

These  vascular  phenomena  were  interpreted  by  Cohnheim  as 
the  essential  inflammatory  attributes  and  he,  therefore,  regarded 
inflammation  as  the  result  of  an  alteration  in  vessel  walls  excited  by 
an  irritant.  He  subordinated  all  other  changes  in  fixed  tissues  as 
being  either  dependent  upon  the  vascular  disturbances,  or  secon- 
dary, concomitant  and  not  necessarily  essential.  The  brilliant  ex- 
periments and  dialectics  of  Cohnheim  gained  him  much  ground, 
and  some  of  his  followers  went  so  far  as  to  deny  any  changes  in 
parenchyma  cells,  or  to  regard  them,  as,  at  least,  negligible. 

Thus  originated  the  modern  idea  of  the  vascular,  interstitial 
character  of  inflammation.  Nevertheless,  these  views  did  not  suc- 
ceed in  replacing  entirely  Virchow's  opinions  and  observations. 
Both  contain  truths  and,  as  in  many  other  scientific  discussions 
where  both  sides  of  an  argument  contain  truth,  both  were  gradu- 
ally accepted,  but  unfortunately  as  distinct  and  different  types  of 
inflammation,  and  it  became  prevalent  to  speak  of  parenchymatous 
and  interstitial  (vascular)  inflammations  in  a  contrasting  sense. 
This  created  a  very  grave  and  fundamental  error  from  which 
pathology  is  still  suffering.  It  was  based  on  the  too  narrow  inter- 
pretations of  Virchow  on  the  one  side,  and  of  Cohnheim  on  the 
other. 

The  situation  has  become  still  further  confused  by  the  attempt 
of  some  pathologists  to  define  inflammation  not  from  the  scientific, 
but  teleological  standpoint,  that  is,  as  a  primarily  intentional, 
useful  effort  of  repair  on  part  of  nature.  But  such  a  standpoint  is  an 
altogether  too  personal  view  of  a  biological  problem. 

On  the  contrary,  we  must  endeavor  to  understand  and  then 
explain  pathological  processes  by  their  genetic  relations  without 
reference  to  anything  outside  of  them,  giving  due  consideration 
to  all  parts,  whether  we  see  anything  useful  in  them  or  not.  In 
fact  the  study  of  inflammation  cannot  be  approached  with  a 
scholastic,  ready  definition.  This  would  adopt  the  faults  of  the  old 
psychology  which  commenced  the  study  of  psychic  phenomena 
with  a  definition  of  the  soul  and  then  arranged  the  facts  to  suit 
that  definition. 

Here  lies  the  point.  The  still  existing  confusion  in  regard  to  the 
conception  of  inflammation  is  due  to  its  complex  character:  neither 


222  GENERAL  PATHOLOGY 

degeneration,  nor  exudation,  nor  its  usefulness  or  harm  can  be 
regarded  as  specific  and  of  distinguishing  character.  It  is  true  that 
at  times  one  or  the  other  of  these,  or  several,  may  predominate, 
but  this  is  variable,  frequently  temporary  and  changeable  in  the 
course  of  an  inflammation.  Lubarsch  expresses  it  well  by  an  apt 
comparison,  in  saying  that  lightning  without  thunder,  wind  and 
rain  does  not  constitute  a  thunder  storm.  So  the  very  conception 
of  inflammation  requires  a  combination  of  processes  and  occur- 
rences whose  only  claim  to  entity  is  their  direct  genetic  relation. 

Inflammation  is  always  the  result  of  an  irritation,  moreover  an 
irritation  which  involves  all  parts  and  cells  of  a  tissue.  This  irri- 
tation must  exceed  the  limits  of  physiological  adaptation  and 
presents,  therefore,  exaggerations  of  impression  by  an  irritant  and 
reactions  by  the  tissues.  All  inflammatory  processes  show,  therefore, 
in  varying  degree  and  combinations,  passive  and  active  features. 
The  entity  as  an  inflammatory  process  depends  not  upon  one  of 
these,  but  the  direct  genetic  relation  of  both. 

In  his  lectures  Virchow  used  to  draw  a  personal  comparison 
which  may  be  cited  in  this  connection:  Three  persons  are  sitting 
quietly  on  a  bench  when  suddenly  a  stone  is  thrown  at  them 
and  injures  one  of  them.  The  other  two  would  be  excited,  not  only 
by  the  sudden  appearance  of  the  missile,  but  also  by  the  injury  of 
their  companion  to  whose  assistance  they  would  hurry.  This  some- 
what nai've  comparison  aptly  illustrates  that  inflammation  is  a 
disturbance  in  local  cell  relations.  One  may  imagine  one  cell  de- 
generated, but  never  inflamed.  Inflammation  requires  tissues. 

Having  thus  appreciated  the  complexity  of  inflammation  and 
having  seen  that  it  is  composed  of  passive,  that  is,  degenerative, 
and  active,  that  is,  vascular  and  proliferative  changes,  we  may  for 
the  sake  of  study,  and  as  emphasizing  certain  phases  of  the  inflam- 
matory lesions,  divide  them  according  to  the  predominating  char- 
acter as  follows: 

1.  Degenerative  inflammation;  in  which  the  insult  to  the  tissue 
is  most  evident  and  controls  the  picture. 

2.  Exudative  inflammation;  in  which  discharge  of  cell  and  fluid 
blood  constituents  is  conspicuous,  important  and  may  put  the 
other  inflammatory  attributes  more  or  less  in  the  background. 


CHANGES  IN  LOCAL  CELL  RELATIONS          223 

3.  Proliferative  and  productive  inflammation,  in  which  prolif- 
eration of  fixed  tissue  cells  and  the  formation  of  inflammatory  new 
tissue  are  prominent  and  control  the  course  and  outcome  of  the 
inflammation. 

It  is  misleading  to  speak,  as  is  still  done  by  some,  of  parenchy- 
matous  and  interstitial  inflammations,  since  we  know  that  in  any 
inflammation  all  tissues  take  part.  Thus,  in  what  is  sometimes 
referred  to  as  interstitial  inflammation,  parenchyma  is  as  much, 
often  earlier  and  more  involved  than  the  interstitial  tissue  and  the 
term  "interstitial"  gives  us  no  idea  of  the  nature  and  genesis  of  the 
lesion.  Only  very  early  it  is  possible  to  trace  and  locate  the  primary 
morphological  inflammatory  expression  in  one  or  the  other  tissue, 
and  even  then  careful  examination  will  reveal  in  almost  every 
instance  involvement  of  parenchymatous  and  interstitial  parts. 

i.  DEGENERATIVE  INFLAMMATION.  The  degenerative  inflamma- 
tion is  characterized,  as  far  as  it  can  be,  by  degenerative  changes 
and  injury  of  parenchyma  cells,  while  exudative  and  proliferative 
phenomena  remain  subordinated.  But  they  are  never  entirely 
lacking  and  with  an  active,  arterial  hyperemia  complete  the  in- 
flammatory requisites.  The  exudate  in  many  of  these  cases  remains 
fluid,  serous  (inflammatory  edema),  and  leads  to  serous  imbibition, 
swelling  and  stretching  of  the  intercellular  tissue.  Tissues  which  are 
the  seat  of  a  degenerative  inflammation  appear,  therefore,  turbid, 
gray,  bulging,  with  normal  markings  indistinct  or  irregular.  Blood 
vessels  are  partly  engorged,  prominent;  partly  obstructed  by  com- 
pression from  parenchymatous  and  intercellular  swelling.  When 
there  is  prominent  injection  of  capillary  districts,  parts  appear 
diffusely  pinkish.  Degenerative  inflammations  often  proceed  to 
more  severe  exudative  inflammations  in  which  the  exudate  assumes 
greater  prominence  and  at  the  same  time  becomes  more  cellular 
(degenerative,  exudative  inflammation). 

Proliferation  of  fixed  tissue  cells  (parenchyma  and  interstitial 
connective  tissue)  remains  generally  quite  limited  in  simple  degene- 
rative inflammation.  In  some  types,  however,  especially  where 
much  desquamation  and  loss  of  cells  occur,  it  may  reach  consider- 
able dimensions  (see  Catarrhal  Inflammation).  These  proliferating 
fixed  tissue  cells  are  not  regenerative  attempts,  but  a  response 


224  GENERAL  PATHOLOGY 

to  an  inflammatory  irritant.  True  regeneration  does  not  commence 
until  the  inflammatory  irritant  and  its  results  have  subsided. 

Inflammatory  cell  proliferation  differs  from  true  regeneration 
by  its  excess  and  disregard  to  physiological  demands.  Regenera- 
tion is  strictly  limited  to  replacement  of  a  loss  in  a  particular 
locality.  Inflammatory  cell  proliferation,  on  the  other  hand,  is 
dictated  by  an  irritant  irrespective  of  local  demands.  Degenera- 
tive inflammation  may  subside  and  heal  entirely,  but  it  frequently 
only  ushers  in  the  severer  and  more  destructive  exudative  in- 
flammations. 

2.  EXUDATIVE  INFLAMMATION.  Inflammatory  exudates  consist 
of  a  more  or  less  prominent  discharge  of  blood  constituents  (plasma 
and  cells)  into  the  surrounding  fixed  tissues.  The  importance  of 
this  vascular  phenomenon  in  inflammations  was  first  clearly  em- 
phasized in  character  and  detail  by  the  experimental  investiga- 
tions of  Cohnheim,  which  have  already  been  alluded  to.  They  can 
easily  be  repeated  and  observed  in  the  exposed  mesentery  of  a 
frog  which  is  spread  and  gently  stretched  on  a  glass  stage  and  then 
examined  under  the  microscope. 

When  an  inflammatory  irritant,  such  as  dilute  acid  (exposure 
to  air  may  be  sufficient),  is  applied  to  the  frog's  mesentery,  a 
regular  sequence  of  vascular  phenomena  occurs.  At  first  a  brief 
blood-vessel  contraction  with  increased  rapidity  of  blood  flow  takes 
place,  followed  rapidly  by  dilatation  of  veins  and  capillaries  and 
slowing  of  the  blood  stream.  At  the  same  time  leucocytes  move 
from  the  axis  of  the  stream  to  the  periphery  and  attach  themselves 
in  increasing  numbers  to  the  walls  of  blood  vessels  while  red  blood 
cells  continue  their  flow  in  the  axial  current.  Soon  emigration  of 
leucocytes  through  the  vessel  wall  into  the  surrounding  structures 
is  noticeable.  Leucocytes  flatten  against  the  interior  of  the  vessel 
wall  and  send  small  protoplasmic  processes  through  the  vessel 
stomata.  Ultimately  the  whole  leucocyte  body  thus  passes  through 
the  wall  and  now  lies  outside  of  the  vessel.  Even  then  they  continue 
their  ameboid  motion  in  the  watery  blood  fluid  which  with  them 
has  left  the  vessel  and,  as  inflammatory  edema,  infiltrates  the 
the  tissues. 

In  strong  inflammatory  irritants  red  blood  cells  and  blood  plate- 


CHANGES  IN  LOCAL  CELL  RELATIONS          225 

lets  also  pass  out  and  may  give  to  this  exudate  a  distinctly  hemor- 
rhagic  character.  The  emigration  of  leucocytes  commences  three 
or  four  hours  after  exposure,  on  an  average  six  to  eight  hours; 
sometimes  it  occurs  late,  after  twelve  to  fifteen  hours.  The  emi- 
grated leucoytes  are  largely  polymorphonuclear  neutrophiles. 
These  predominate  in  the  very  acute,  severe  exudations  and  furnish 
the  bulk  of  pus  cells.  Lymphocytes  and  mononuclear  cells  appear 
in  milder  irritants  and  also  in  certain  specific  inflammations  such  as 
in  tuberculosis,  scarlet  fever,  syphilis,  and  some  other  infective 
granulomata  (see  later).1 

Sometimes  emigration  of  lymphocytes  precedes  or  accompanies 
that  of  the  polymorphonuclear  variety,  giving  rise  to  mixed  pus. 
Lymphocytes  and  other  mononuclear  cells  occasionally  undergo 
cell  changes  in  tissues  to  so-called  "plasma"  cells  (cells  with  smooth, 
supple  protoplasm  and  eccentric  nuclei)  and  large  clasmatocytes. 
These  are  called  collectively  polyplasts  or  leucocytoid  cells  (see 
also  under  Productive  Inflammation). 

The  whole  process  of  inflammatory  exudation  was  formerly 
regarded  as  chemiotactive  in  origin,  that  is,  due  to  chemical 
attraction  of  leucocytes  by  inflammatory  irritants.  It  is,  how- 
ever, probably,  at  least  largely,  a  physical  phenomenon  de- 
pending upon  changes  in  surface  tension  in  the  inflamed  tissues 
from  necrotic  and  degenerative  cell  products.  These,  as  already 
explained  in  the  paragraph  on  immunity,  lower  surface  tension  in 
the  involved  parts  and  thus  leucocytes  and  other  migrating  cells 
move  towards  the  lowest  tension.  Surface  tension  changes  and 
equalization  are  probably  also  responsible  for  morphological 
changes  in  cells  after  emigration  (plasma  cells)  and  the  formation 
of  giant  cells. 

Exudative  inflammations  are  frequently  ushered  in  or  preceded 
by  degenerative  inflammation  or  from  the  start  associated  with 
it.  The  severity  and  quality  of  the  irritant  and  consequent 
injury  to  the  vessel  wall,  of  course,  vary  and,  therefore,  also  the 
character  of  the  exudate.  Consequently  exudative  inflammations 

1  These  mononuclear  cells  constitute  so-called  "small  round-celled  infiltra- 
tion.*'   Some  of  these  are  undoubtedly  also  derived  from  proliferating  fixed 
connective  tissue  and  endothelial  cells. 
15 


226  GENERAL  PATHOLOGY 

may  be  classified  according  to  the  character  of  the  exudate.  But 
this  is,  by  no  means,  fixed  and  combinations  are  irequent. 

Characters  oj  Exudates.  (a)  Serous  exudate,  or,  as  it  is  frequently 
referred  to,  inflammatory  edema,  is  a  frequent  accompaniment  of 
simple  degenerative  inflammations.  This  exudate  is  fluid,  clear, 
contains  only  few  cells,  but  is  richer  in  albumin  and  thicker  than 
serum  or  lymph.  Moreover,  it  is  morphologically  always  associated 
with  active,  arterial  hyperemia  or  vessel  engorgement.  The  exudate 
permeates  the  fixed  tissues,  separates  them,  swells  them  and  is  at 
least  partly  imbibed  by  them  (Virchow's  excessive  nutrient  fluid; 
this  is  sometimes  spoken  of  as  inflammatory  hydrops).  Generally 
speaking  serous  exudate  is  poor  in  fibrin  and  does  not  readily 
coagulate.  Serous  exudate  is  often  only  the  first  or  initial  stage 
of  a  cellular  or  fibrinous  exudate  which  is  richer  in  cells,  fibrin 
and  albumin  contents  and  comes  nearer  to  blood  plasma.  Some 
inflammatory  irritants  lead  to  a  tremendous  inflammatory  edema 
or  serous  exudate  with  many  red  cells  (hemorrhagic),  but  relatively 
few  leucocytes  (anthrax,  malignant  edema,  some  streptococcus 
strains,  influenza,  etc.,  also  some  poisons,  trinitrotoluene,  uranium 
nitrates,  etc.). 

Serous  exudate  differs  from  simple  edema  (see  later)  by  higher  al- 
bumen and  cell  contents  and  the  accompanying  arterial  congestion. 

(b)  Catarrh al-mucoid   exudate  is   confined  to  surfaces,   either 
of  a  mucous  membrane  or  to  lining  of  a  glandular  lumen  or  duct. 
It  is  a  mixture  of  an  inflammatory  hypersecretion  with  serous  or 
cellular  blood  exudates  and  leads  to  swelling  and  desquamation 
of  the  living  cells  of  the  surface  (catarrh).  The  catarrh  thus  pro- 
duced is  simple  but  it  may  become  purulent  by  addition  of  pus 
cells,  or  hemorrhage  by  free  discharge  of  red  blood  cells  from  en- 
gorged and  often  bursting  capillaries  into  the  catarrhal  and  mucoid 
exudate. 

(c)  Hemorrbagic  is  an  exudate  which  contains  a  sufficient  num- 
ber of  red  cells  to  color  it  distinctly.  This  is  due  either  to  a  direct 
discharge  of  these  cells  through  the  vessel  walls  (occurs  in  severe 
and  certain  specific  inflammations)  or  due  to  rupture  of  smaller 
blood  vessels  from  the  inflammatory  engorgement  through  the 
injured  wall.  This  latter  is  really  more  correctly  hemorrhage  into 


CHANGES  IN  LOCAL  CELL  RELATIONS        (22 


an  exudate,  but  often  indistinguishable  from  true  diapedesis  (pas- 
sage) of  blood  cells  through  the  unbroken  vessel  wall.  It  is  char- 
acteristic of  certain  tuberculous  infections,  streptococcus  infections 
and  when  tumors  (cancers)  lead  to  inflammatory  changes  in  the 
tissues  which  they  inhabit  or  infiltrate. 

(d)  Purulent  is  an  exudate  in  which  leucocytes,  especially  poly- 
morphonuclears  are  present  in  such  large  quantities  as  to  render 
the  exudate  opaque,  thick,  yellowish  or  creamy.  Usually  it  occurs 
without  fibrin  (Pus  bonum  et  laudabile  of  the  older  writers), 
but  occasional^,  especially  in  some  infections  and  locations,  with 
fibrin.  Pus  cells  are,  therefore,  leucocytes,  either  still  living  and 
motile  or  dead,  fatty,  disintegrating.  At  first  pus  cells  accumulate 
around  blood  vessels  and  can  be  seen  to  emigrate  from  them  (peri- 
vascular  foci),  they  then  move  along  perivascular  lymph  sheaths. 
Gradually  they  infiltrate  the  tissue,  become  more  diffuse  and  fre- 
quently bring  the  fixed  tissue  to  necrosis  and  softening.  Localized, 
circumscribed  accumulations  of  pus  in  disintegrated  tissues  which 
fuse  with  the  exudate  are  spoken  of  as  abscesses.  The  wall  of  the 
abscess  is  usually  under  tension  from  inflammatory  edema  and 
hyperemia.  Occasionally  coagulated  pus  and  fibrin  may  form  a 
coating  around  the  inner  abscess  cavity  (pyogenic  membrane). 
The  cavity  may  break,  usually  toward  a  surface  (least  resistance), 
purulent  contents  and  tissue  detritus  are  discharged  and  an  ulcer 
is  left  which  heals  by  granulation.  Pus  may  also  be  poured  into  nor- 
mal cavities — pericardium,  pleura,  peritoneum,  gall  bladder,  etc. 
This  is  spoken  of  as  empyema  of  a  respective  cavitv. 

Diffuse,  not  well  localized,  purulent  infiltrations  which  involve 
the  deeper  structures  of  a  part  or  organ  in  necrosis  and  softening 
are  spoken  of  as  phlegmon.1 

Skin  phlegmons  are  sometimes  spoken  of  as  furuncles;  when 
multiple  as  furunculosis,  but  in  some  of  these  the  skin  involve- 
ment is  apparently  secondary  to  infection  and  inflammatory  necro- 
sis of  subcutaneous  parts  (Embolic  Infections). 

1  From  <t>\eynov?i  —  purulent  inflammation:  excess  of  phlegm.  The  term 
cellulitis  still  used  by  many  as  a  name  for  this  lesion  is  most  objectionable  in 
meaning,  derivation  and  construction.  Cells  cannot  become  inflamed,  only 
issues. 


228  GENERAL  PATHOLOGY 

Secondary  complications  in  diffuse  purulent  inflammations  or 
localized  abscesses  with  stagnant  pus  and  necrotic  masses  are 
hemorrhage  or  infections  with  putrefactive  bacteria.  Then  gan- 
grene and  sloughing  follow. 

Purulent  exudates  are  most  frequently  the  result  of  infections 
with  so-called  pyogenic  micro-organisms — staphylococci,  and  gono- 
cocci — but  other  bacteria  like  bacillus  coli,  typhoid,  etc.,  may  also 
be  concerned.  The  gonococcus  produces  a  pus  rich  in  large  plasma 
cells  along  with  ordinary  polymorphonuclears.  In  early  purulent 
exudates  eosinophiles  and  large  mononuclear  cells  are  apt  to  pre- 
dominate and  sometimes  continue.  Generally  they  are  superseded 
soon  by  the  neutrophiles. 

In  abscesses  and  purulent  infiltrations  the  organisms  which  are 
etiologically  concerned  may  often  be  demonstrated  in  the  exudate 
or  by  culture;  not  infrequently,  however,  such  exudates  are  sterile, 
especially  in  older  foci,  because  bacteria  have  been  destroyed  or 
have  succumbed  in  the  necrotic  areas  for  want  of  proper  food 
supply  or  change  in  the  reaction  of  the  medium,  antibodies,  etc. 
(especially  true  of  strictly  pathogenic  forms). 

Besides  these  organized  causes  of  purulent  inflammations,  certain 
strongly  toxic  irritants  may,  when  locally  applied,  lead  to  typical 
purulent  exudates,  more  especially  turpentine  and  croton  oil. 

(e)  Fibrinous  is  an  exudate  rich  in  fibrinogen  which  after  exuda- 
tion rapidly  coagulates  into  interwoven  threads  or  so-called  pseudo- 
membranes.  It  occurs  as  a  result  of  intense  inflammatory  irritants, 
usually  on  the  surface  of  mucous  membranes  or  on  the  inner  lining 
of  glandular  alveoli  (lung  in  pneumonia)  and  is  often  combined 
with  a  purulent  or  hemorrhagic  admixture. 

It  is  customary,  following  Virchow's  precedent,  to  make  two 
divisions  of  this  exudate: 

(A)  Croupous,  under  which  term  are  included  all  uncomplicated 
fibrinous  exudates  in  which  the  fixed  tissue  below  the  exudate 
becomes  only  superficially  necrotic  and  fuses  with  it  (croupous 
membrane).  It  is  held  that  here  the  inflammatory  necrosis  of  the 
lining  cells  gives  rise  to  a  ferment  which  coagulates  fibrinogen  to 
the  solid  form.  The  croupous  membrane  is,  therefore,  composed  of 
a  fine  fibrin  network  with  some  necrotic  material  which  is,  on  the 
whole,  easily  removed  from  its  attached  surface. 


CHANGES  IN  LOCAL  CELL  RELATIONS          229 

(B)  Diphtheritic  or  true  pseudo-membranous,  under  which  term 
are  included  those  severe,  intense  fibrinous  inflammations  in  which 
deep  necrosis  of  the  fixed  tissues  occurs  and  in  which  an  abundance 
of  fibrinous  exudate  fuses  with  the  necrosed  parts  (coagulation 
necrosis)  to  form  a  thick,  firmly  attached  pseudo-membrane  on 
surface  of  an  organ.  These  pseudo-membranes  are,  therefore, 
removed  with  difficulty  and  leave  an  irregular,  deep,  bleeding 
base  with  considerable  loss  of  substance  (diphtheritic  inflamma- 
tion). The  dead  pseudo-membrane  undergoes  often  secondary 
changes,  becomes  gangrenous,  greenish,  incrusted  with  salts  and 
may  then  be  almost  impossible  to  separate  from  its  attachment 
(for  example,  in  diphtheritic  cystitis  of  urinary  bladder). 

Diphtheritic  inflammations  are  often  excited  by  the  Klebs- 
Loffler  bacillus  (see  it)  but  not  exclusively  so.  They  may  be  due  to 
other  infections  such  as  scarlet  fever,  influenza  etc.,  or  to  poison- 
ous fumes  or  gases.  In  stomach  and  gut  they  occur  in  dysentery, 
uremia  and  certain  metallic  poisonings,  for  example,  bichloride  of 
mercury.  They  result  here  from  excretion  of  such  poisons  by  the 
lower  gut  (excretory  ulcerative  colitis) . 

3.  PRODUCTIVE  INFLAMMATION.  Under  productive  inflamma- 
tions we  include  those  inflammations  which  are  characterized 
by  an  abundant,  impressive  proliferation  of  parenchyma  cells, 
of  the  connective-tissue  stroma,  or  of  both.  These  inflammations 
may  again  be  subdivided  into  simple,  proliferative  and  genuine 
productive  forms.  In  the  first  occurs  only  abundant  proliferation 
of  cells.  In  the  second,  cells  mature  and  organize  to  a  new,  inflam- 
matory tissue.  The  former  is  characteristic  of  certain  types  of  acute, 
rapid  or  desquamating  inflammations  (catarrh)  on  outer  or  inner 
surfaces,  also  of  certain  specific  infections  such  as  typhoid  or  tuber- 
culosis. The  latter,  of  slowly  progressing,  less  intense,  chronic  in- 
flammations in  which  newly  formed  cells  have  opportunity  to 
mature  and  to  combine  to  a  tissue.  For  these  reasons  degenerative 
and  exudative  processes  appear  here  subordinated  and  less  promi- 
nent than  the  productive  changes. 

The  productive-inflammations  acquire  great  importance  by  their 
gradual,  but  persistent  and  progressive  destruction  of  normal 
parenchyma  and  its  replacement  by  inflammatory  granulation 


230  GENERAL  PATHOLOGY 

and  scar  tissue.  The  whole  anatomical  arrangement  and  tissue 
plan  is  thereby  reconstructed  and  remaining  parts  of  parenchyma 
are  put  into  an  abnormal,  new  environment.  Their  physiological 
continuity  and  relations  are  interrupted  by  the  growth  of  inflamma- 
tory tissue.  Thus,  parenchyma  cells  alter  their  shape,  proliferate 
to  new  abnormal  types  of  cells  and  establish  new  connections. 
The  anatomical  alterations  assume,  therefore,  a  qualitative  charac- 
ter and  restitution,  even  to  relative  integrity,  is  here  out  of  question. 
Even  gross  appearances  and  organ  forms  are  changed. 

The  slower  the  progress,  the  greater  the  possibility  of  adapta- 
tion by  the  whole  organism  to  the  changing  conditions  in  these 
inflamed  organs  and  to  the  necessarily  resulting  disturbance  in 
general  constitutional  balance.  Thus  it  happens  that  slowly  pro- 
gressing productive  inflammations,  even  in  important  organs 
(liver,  kidney)  are  compatible  with  longer  life  than  the  acute, 
rapidly  destructive  types.  In  the  end,  however,  they  kill,  if  affecting 
vital  organs,  by  reason  of  their  steady,  unhalting  progress  which 
ultimately  removes  an  organ  entirely  from  its  connection  with  the 
physiological  sphere  of  other  interrelated  organs.  This  will  be  dis- 
cussed more  fully  in  a  subsequent  paragraph  on  inflammatory  tis- 
sue formation  and  inflammatory  organ  reconstruction. 

4.  COURSE  AND  TERMINATION  OF  INFLAMMATIONS.  The  course 
of  inflammations  depends  upon: 

1.  The  quality  of  the  inflammatory  irritant  and  its  concentration 
as  well  as  the  area  involved  by  it.  In  smaller  surfaces  the  course  is 
apt  to  be  quicker;  also  when  the  irritant  is  of  mild  character  or  acts 
in  great  dilution. 

2.  Time  of  Action.     The  length  of  time  over  which  an  irritant  is 
allowed  to  act  is  of  great  importance  in  relation  to  the  course  and 
severity  of  an  inflammation.  Thus,  immersing  the  ear  of  a  rabbit 
in  water  of  only  48°  to  56°C.,  it  is  possible,  by  varying  the  time  of 
exposure,  to  obtain  all  degrees  of  inflammation  from  simple  hypere- 
mia  to  necrosis  and  sloughing. 

3.  The  Condition  of  the  Inflamed  Tissue.    This  depends,  partly, 
upon  the  character  and  severity  of  the  inflammatory  changes  them- 
selves, that  is,  the  quality  and  extent  of  the  degeneration  and 
destructive  changes,  the  character  (solid  or  fluid)  of  the  exudate, 


CHANGES  IN  LOCAL  CELL  RELATIONS          231 

finally,  upon  obstruction  or  clearance  of  vessels  and  lymph  spaces 
which  are  required  for  the  removal  and  resorption  of  softened 
inflammatory  products;  partly  too,  upon  the  condition  of  tissues  at 
the  time  of  inflammation.  Anemia,  atrophy  and  paralysis  with  poor 
nutrition  allow  tissues  to  succumb  more  readily  to  an  irritant,  heal 
less  readily,  and,  therefore,  prolong  the  course  of  an  inflammation. 

Terminations  of  inflammations  are,  of  course,  intimately  con- 
nected with  the  cause.  An  inflammation  either  heals,  or  it  does  not 
heal  and  becomes  chronic  or  long  continued. 

i.  Healing  of  an  inflammation  may  be  complete  and  absolute,  i 
Here  occurs  restitution  to  former  anatomical  and  physiological 
value.  It  may  be  incomplete  or  relative  through  insufficient  or 
faulty  regeneration  of  physiological  tissues  and  substitution  by  a 
tissue  of  inferior  quality  (fibrous  connective  tissue,  scar).  Complete 
or  absolute  restitution  to  integrity  requires:  (i)  removal  of  the 
inflammatory  irritant;  (2)  removal,  resorption  of  inflammatory 
products;  (3)  preservation  of  normal  architectural  scaffold  and 
replacement  within  this  of  the  injured  or  destroyed  tissue  by  one 
of  equal  value  and  composition. 

The  first  of  these  requisites  is  carried  out  by  destruction  and 
annihilation  of  the  irritant  by  local  cell  action  or  general  antibody 
formation,  or  by  physical  alterations  in  tissue  constitution. 

The  second  depends  upon  softening  of  inflammatory  products 
(ferment  action  of  leucocytes),  their  liquefaction  and  removal  by 
lymphatics.  This  is,  of  course,  more  easily  done  in  semifluid  exu- 
dates  (pus)  than  in  dry,  coagulated  pseudo-membranous  deposits. 
It  also  requires  clearing  of  lymphatics.  As  long  as  these  are  com- 
pressed and  themselves  clotted  by  inflammatory  masses,  resorp- 
tion of  an  exudate  is,  of  course,  impossible.  Larger  dead  parts  are 
sometimes  cast  off  en  masse,  sequestration  (bone,  gangrene),  after 
which  the  defect  is  covered  by  granulations  and  later  scar 
tissue. 

The  third  requisite,  preservation  of  physiological  architecture 
and  regeneration  of  new  cells  of  equal  physiological  value,  depends 
upon  the  two  preceding  factors.  The  longer  in  time  and  more  ex- 
tensive an  inflammation,  the  less  chance  of  restitution  to  integrity. 
By  destruction,  or  from  collapse,  of  the  architectural  arrangement, 


232  GENERAL  PATHOLOGY 

regenerative  attempts  become  incomplete,  aborted,  atypical, 
irregular  and  the  outcome  pathological.  Such  instances  are  often 
associated  with  excessive  scar  tissue  formation  which  replaces  the 
incompletely  formed  parenchyma  cells  and  the  lost  architecture. 
Healing  under  those  conditions,  is,  therefore,  far  from  being  true 
restitution  to  integrity,  it  is  rather  an  ending  by  cicatricial  replace- 
ment of  disorganized  parts.  This  gradually  shades  into: 

2.  When  an  inflammation  is  prevented  from  healing,  because 
the  inflammatory  irritant  is  not  completely  removed,  but  con- 
tinues in  attenuated,  lessened  intensity,  or  when  inflammatory 
products  cannot  be  removed  for  one  or  the  other  reason,  inflamma- 
tion becomes  prolonged  and  assumes  clinically  a  chronic  course.  The 
chronic  inflammations  are  essentially  productive  with  not  infre- 
quent exacerbations  in  degenerative  or  exudative  processes.  They 
offer  a  great  variety  of  anatomical  and  clinical  pictures  for  they 
lead,  as  has  already  been  emphasized,  to  entire  organ  reconstruc- 
tion. The  organ  is  gradually  removed  further  and  further  from  the 
physiological  sphere  and  becomes  foreign  to  the  rest  of  the  body 
and  its  physiological  relations.  All  the  processes  which  in  combina- 
tion go  to  form  this  new  pathological  unit  are  grouped  under  the 
heading  of  inflammatory  tissue  formation. 

5.  INFLAMMATORY  TISSUE  FORMATION  AND  INFLAMMATORY 
ORGAN  RECONSTRUCTION.  In  a  previous  paragraph  (§3,  Produc- 
tive Inflammations)  reference  was  made  to  certain  inflammations 
in  which  proliferation  of  connective  tissue  and  parenchyma  cells 
leads  not  only  to  the  formation  of  new  cells,  but  also  to  organization 
of  a  permanent,  new,  foreign  tissue.  The  original,  normal  parenchy- 
ma is  lost,  obliterated  and  replaced  by  newly  formed  inflammatory 
tissues.  Thus  the  architecture  of  these  organs  is  entirely  recon- 
structed, their  functions  correspondingly  altered  and  a  new  patho- 
logical organ  or  unit  created.  The  growth  of  connective  tissue  is 
either  very  pronounced  and  diffuse,  or  patchy,  irregular  and  vari- 
able in  distribution.  As  it  is  derived  from  the  interstitial  organ 
stroma  these  inflammations  have  been  referred  to  as  interstitial. 
But  this  is  misleading,  for  the  increase  in  interstitial  fibrous  tissue 
is  only  one  part  or  feature  of  this  inflammation.  Equally  great  and 
important  is  the  associated  degenerative  waste  of  parenchyma 


CHANGES  IN  LOCAL  CELL  RELATIONS          233 

which  is  combined  with  atypical  proliferation  of  parenchyma  cells 
and  reconstruction  of  remaining  parenchyma  parts. 

Histogenetically  the  growth  of  new  connective  tissue  resembles 
granulation  tissue,  but  is  distinguished  by  excessive  and  progressive 
growth  which  is  not  limited  by  the  necessities  of  covering  a  defect. 
It  exhibits  a  greater  and  more  irregular  activity  in  cell  prolifera- 
tion, advancing  by  leaps  and  bounds  even  into  areas  which  have 
as  yet  not  lost  their  parenchyma.  Moreover,  mature  parts  may 
suddenly  become  again  cellular,  young  and  reactivated  (inflam- 
matory stimulant).  Inflammatory  granulation  tissue  is  rich  in 
fibroplasts  and  derivatives  of  lymphocytes  which  develop  after 
^emigration  into  plasma  cells,  large  leucocytes  and  giant  cells. 
Other  mononuclear  cells  may  be  of  endothelial  derivation.  Thus 
inflammatory  granulation  tissue  compares  with  the  more  regular, 
rapid  maturation  of  healing  granulation  tissue  which  proceeds  in 
orderly  sequence. 

Inflammatory  granulation  tissue  also  forms  a  scar,  but  this 
varies  in  maturity  and  is  never  complete.  In  some  of  the  rapidly 
progressing  productive  inflammations  the  scar  tissue  is  never 
mature,  always  cellular  and  fibroplastic.  In  others  which  proceed 
slowly  and  gradually,  it  assumes  greater  maturity  and  is  less  cel- 
lular. But  in  any  case  it  steadily  advances  and  encroaches  more 
and  more  upon  the  parenchyma. 

The  parenchymatous  changes  which  go  pari  passu  with  the  in- 
crease in  fibrous  tissue  consist  either  of  a  more  or  less  diffuse  rapid 
degeneration  and  loss,  or  a  slow,  more  or  less  localized,  atrophy  in 
which  cells  remain  better  preserved.  The  place  of  wasted  paren- 
chyma is  taken  by  the  spreading  inflammatory  granulation  tissue. 
If  it  advances  rapidly,  which  generally  corresponds  to  equally 
rapid  parenchymatous  destruction,  it  remains  young  and  cellular, 
if  its  progress  is  retarded  with  a  corresponding  slow  parenchyma- 
tous waste,  it  matures  to  greater  perfection. 

In  any  case  parts  of  parenchyma  are  thus  detached  and  separated 
from  others,  lose  continuity  and  contact  of  structure  and  rela- 
tions and  are  placed  in  an  isolated  new  environment.  From  this 
point  on  regenerative  attempts  in  parenchyma  assume  atypical 
manner  and  are  very  imperfectly  and  abnormally  performed. 


234  GENERAL  PATHOLOGY 

Old  and  new  cells  of  these  parts  arrange  themselves  in  new, 
often  very  foreign,  fashion.  Old  physiological  channels  of  nutri- 
tion, secretion  and  excretion  are,  at  least  partly,  obliterated, 
partly  changed  in  course  and  distribution.  Thus  the  detached 
parts  produce  not  only  new  cells  and  tissues,  but  establish 
new  communications  with  their  surroundings.  Ultimately  the 
whole  organ  is  transformed  into  a  new  pathological  entity, 
strange  and  no  longer  adapted  to  the  physiological  union  of  the 
whole  organism. 

I  have,  in  the  progress  of  this  discussion,  repeatedly  empha- 
sized this  point  on  account  of  its  functional  importance,  for  it  is 
evident  that  functions  of  these  inflamed  organs  do  not  merely  rep- 
resent quantitative  shiftings  on  a  sliding  physiological  scale.  New 
conditions  arise  through  a  more  or  less  complete  cell  and  archi- 
tectural reformation.  It  is  one  of  the  most  important  fields  of 
modern  pathological  morphology  to  reconstruct  the  plan  of  these 
organs,  for  their  architecture  holds,  as  in  the  physiological  prototype, 
the  key  for  the  understanding  of  pathological  function.  Thus,  our 
understanding  of  the  functional  disturbances  in  productive  inflam- 
mations in  kidney  and  liver  has  recently  been  much  advanced  by 
a  better  knowledge  of  their  organization. 

It  has  been  stated  that  all  productive  inflammations  are  char- 
acterized by  waste  of  parenchyma  and  growth  of  inflammatory 
granulation  or  scar  tissue.  The  question  of  the  genetic  relation  of 
the  two  has  been  much  discussed.  Weigert  took  the  view  that  the 
connective  tissue  formation  is  entirely  reparative  and  follows 
parenchymatous  loss.  A  similar  view  had  been  already  expressed 
by  Virchow,  and  some  modern  pathologists  (Aschoff)  go  so  far  as 
to  divorce  the  scar  tissue  growth  from  the  inflammatory  attri- 
butes. These  extreme  ideas  seem  to  me  incorrect,  for  the  formation 
of  inflammatory  granulation  tissue  occurs  prominently  and  abun- 
dantly at  early  stages  when  destruction  and  loss  of  parenchyma 
are  as  yet  absent  or,  at  least,  not  sufficiently  advanced  to  call  for 
such  extensive  compensatory  growth.  We  also  know  that  loss  of 
parenchyma,  as  in  atrophy,  is  not  in  every  instance  followed  by 
granulation  tissue  replacement. 


CHANGES  IN  LOCAL  CELL  RELATIONS          235 

On  the  other  hand,  we  cannot  entirely  share  Ziegler's  opposite 
view,  who  looks  upon  the  production  of  inflammatory  granulation 
tissue  as  the  primary  lesion  and  holds  that  its  growth  strangles  the 
parenchyma.  In  the  first  place  it  would  appear  that  a  perfectly 
healthy  parenchyma  would  oppose  this,  and  in  the  second  and 
more  important  place,  it  is  generally  possible  to  detect  in  early 
productive  inflammations  at  least  slight  and  localized  degenerative 
changes  in  the  parenchyma.  These  do  not  depend  upon  encroach- 
ment by  inflammatory  granulation  tissue. 

It  seems,  therefore,  nearer  the  truth  to  regard  both  lesions  as 
coordinated  expressions  of  the  action  of  an  inflammatory  irritant. 
This  excites  the  connective  tissue  to  growth  when  at  the  same  time 
it  leads  parenchyma  to  destruction.  According  to  this  view  both 
are  correlated,  equally  essential  parts  of  production  inflammation. 

6.  CONCLUSIONS.  We  have  now  reached  the  point  to  enter 
upon  a  definition  of  inflammation.  We  have  seen  that  it  is  an 
extremely  complex  combination  of  degenerative,  exudative,  pro- 
liferative  and  productive  processes  which  associate  in  different 
degrees  and  qualitative  modifications.  All  efforts  to  regard  inflam- 
mation as  an  expression  of  only  one  or  the  other  of  these 
components  must  fail  for  it  is  their  very  combination  which 
makes  them  inflammatory.  Attempts  have  also  been  made  to 
trace  all  inflammatory  processes  to  one  common  origin;  some 
look  upon  degenerative  lesions  as  the  cause  of  exudation  and  pro- 
liferation, others,  again,  look  upon  the  exudative  phenomena  as 
the  precursors  of  degenerations.  All  these  finer  distinctions  cannot 
be  elevated  to  fixed  generalizations.  It  is  difficult  to  trace  absolute 
dependence  of  one  upon  the  other  in  early  individual  cases,  in  the 
once  established  inflammatory  lesions  it  is  entirely  blotted  out 
and  irrelevant. 

Lastly,  in  defining  inflammation  we  cannot  then  be  satisfied  to 
regard  it  as  purely  passive,  degenerative,  or  purely  active,  vascular 
and  proliferative,  or  finally  as  a  reparative,  defensive  or  useful 
process,  but  an  expression  of  the  sum  total  of  all  those  genetically 
related  degenerative,  exudative  and  productive  processes  which 
are  excited  by  irritants.  We  may  add  that  some  of  these  are 
individually  destructive,  others  helpful. 


236  GENERAL  PATHOLOGY 

7.  INFECTIVE  GRANULOMATA.  Under  the  term  of  infective 
granulomata  are  included  a  number  of  productive  inflammations  of 
specific  etiology  and  characteristic  morphological  behavior 
somewhat  resembling  growth  of  granulation  tissue.  They  occur 
frequently  in  nodular,  tumor-like  multiple  growths  (therefore 
granulomata),  but  are  sometimes  diffuse  and  infiltrating.  Their 
morphology  is  generally  sufficiently  characteristic  to  allow  recogni- 
tion of  the  specific  type;  in  some  instances,  however,  this  is  not 
possible  and  the  etiology  can  only  be  established  with  certainty  by 
identifying  the  etiological  factor  in  the  granulomatous  tissue  or  by 
culture.  At  times  even  this  fails.  We  may  recognize  eight  groups  of 
these  specific  processes: 

1.  Tuberculous  inflammation, 

2.  Syphilitic  inflammation, 

3.  Leprous  inflammation, 

4.  Actinomycotic  inflammation, 

5.  Glanders, 

6.  Rhinoscleroma, 

7.  Blastomycosis, 

8.  Infective  granulomata  of  unknown  etiology. 

i  .  Tuberculous  inflammations  are  excited  by  the  tubercle  bacillus. 
We  must  distinguish  between  the  direct  action  of  the  bacillus  and 
the  action  of  its  toxins.  To  them  are  generally  added  the  activities 
of  partners  in  the  infection,  mixed  infection. 

The  tubercle  bacillus  gives  rise  to  a  nodular  granuloma,  the 
tubercle  —  a  sort  of  granulation  tissue.  Most  conspicuous  in  the 
typical  tubercle  are  generally  elongated  cells  of  flat,  pale,  "epithe- 
lioid"  appearance.  Later  accumulate  mononuclear,  lymphoid 
cells  usually  at  the  periphery  of  the  nodule  so  that  they  surround 
the  paler  "epithelioid"  center  like  a  mantle.1  This  granulation 
tissue  differs  from  non-specific  granulation  tissue  by  complete 
absence  of  embryonic  blood  vessels  and  displays  from  the  start 
an  unfinished,  unhealthy  appearance  which  can  be  attributed  to 
avascularity  and  to  the  toxic  action  of  the  bacilli  on  the  pro- 
liferating fixed  tissue  cells.  The  center  or  periphery  of  the  epithe- 
lioid cells  frequently  shows  characteristic  giant  cells,  i.e.,  large, 


of  these  so-called  "lymphoid"  cells  are  young  fixed  tissue  cells.  (See 
footnote,  page  225.) 


CHANGES  IN  LOCAL  CELL  RELATIONS          237 

smooth,  homogeneous  protoplasmic  bodies  with  a  rather  char- 
acteristic peripheral  arrangement  of  nuclei  or  nuclear  fragments  in 
the  form  of  a  semicircle  (Langhans*  cells).  Suitable  staining 
methods  show  frequently  tubercle  bacilli  in  their  bodies.  They 
originate  by  fusion  of  fixed  cells,  some,  possibly,  also  by  cell 
growth  in  which  division  of  protoplasm  does  not  keep  pace  with 
the  more  rapid  division  of  nuclei.  The  epithelioid  cells  rest  in  a 
fine  reticular  network  derived  from  old  split  connective  tissue 
fibers  or  from  fibrillae  of  the  epithelioid  cells  themselves.  The 
derivation  of  the  epithelioid  cells  in  the  tubercle  has  been  a  source 
of  much  discussion.  Many  investigators  regard  them  as  of  connec- 
tive tissue  origin,  but  others,  notably  Kockel  and  more  recent 
authors,  derive  them  entirely  from  vascular  endothelium.  Experi- 
ments by  Kockel  demonstrate  early  thrombosis  and  obliteration 
of  older  blood  vessels  in  the  tubercle.  He  attributes  the  lack  of 
new  blood  vessels  in  tuberculous  granulation  tissue  to  extreme 
proliferation  of  vascular  endothelium  as  the  result  of  the  tuberculous 
irritant,  and  argues  that  endothelium  proliferates  in  tuberculous 
granulation  tissue  as  in  any  other  granulation  tissue,  but  owing  to 
the  stoppage  in  flow  of  blood  and  its  vis-a-tergo,  this  proliferation 
takes  the  form  of  sheets  and  cords.  These  then  go  to  make  the 
tubercle.  This  view  is  lately  supported  by  Foot  who  also  derives 
epithelioid  cells  from  endothelium,  and  Winternitz  and  others  who 
in  the  liver  trace  the  origin  to  endothelium  of  sinusoids.  The 
local  fibroplastic  reaction  seems  to  occur  later.1 

The  structure  and  fate  of  a  tubercle  and  of  tuberculous  in- 
flammations generally  depend  much  upon  the  strain  and  number 
of  bacilli  and  their  toxine  production.  The  slower  the  growth  of 
a  tubercle,  the  greater  its  contents  in  epithelioid  and  giant  cells, 
but  early  tubercles  and  those  situated  around  blood  vessels  are 
occasionally  made  up  almost  entirely  of  emigrated  lymphocytes. 
In  them  epithelioid  cells  appear  later  and  in  smaller  numbers; 
they  may  even  be  absent. 

Tubercles  are  surrounded  generally  by  a  localized  fibrinous  exu- 
date.  This  exudate,  which  may  be  entirely  lacking,  varies  in  extent 
and  is  the  result  of  vascular  injury  by  the  tuberculous  toxine.  This 

Jobbers  has  quite  recently  advanced  the  view  that  the  "epithelioid  cells" 
are  largely  toxic  disintegration  products  of  the  fixed  tissue  cells. 


238  GENERAL  PATHOLOGY 

diffuses  from  the  nodule  to  the  surrounding  tissue.  In  some  strains 
of  tubercle  bacilli  in  which  toxine  production  is  weak  or  lacking, 
the  exudative  processes  around  the  tuberculous  granulation  are 
very  slight  or  even  absent.  This  is  the  case  in  the  bovine  type,  and 
also  in  some  strains  of  the  human  bacillus.  In  others  it  may  be  so 
strong  as  to  involve  a  considerable  distance  around  the  tubercle 
in  exudative  inflammation  (cheesy  pneumonia). 

Characteristic  is  the  fate  of  the  tubercle  and  of  the  tissue  it 
occupies.  It  undergoes  central  coagulation  necrosis  (cheesy  degen- 
eration) which  increases,  spreads  and  transforms  the  tuberculous 
granulation  tissue  and  the  part  it  inhabits  into  a  clumpy,  dead, 
structureless  mass.  This  spreading  coagulation  necrosis  is  largely 
the  result  of  tuberculous  toxine,  and  its  effect  is  aided  by  the 
entire  avascularity  of  the  tuberculous  granulation  tissue.  A  tend- 
ency to  degeneration  and  necrosis  is,  therefore,  evident  from  the 
start,  in  the  tuberculous  granuloma,  but  the  degree  varies  evi- 
dently with  the  amount  of  toxine  produced  by  different  strains  of 
tubercle  bacilli.  Some  tubercles  never  show  complete  caseation, 
but  rather  growth  of  a  poorly  nourished,  unhealthy,  or  incom- 
pletely developed,  fibrillar  granulation  tissue,  which  occasionally 
fuses  to  a  hyaline  scar.  In  this  way  tubercles  may  be  gradually 
replaced  by  the  scar  and  this  is  regarded  as  healed  tuberculosis 
(may  become  again  active).  On  the  other  hand  the  tuberculous 
caseation  may  proceed  rapidly  and  in  these  cases  of  greater  tox- 
icity  exudative  features  are  more  pronounced  and  the  process 
spreads,  becomes  diffuse  and  presents  a  mixture  and  fusion  of 
caseating  tuberculous  granulation  and  cheesy  gelatinous  disinte- 
grating exudate. 

It  appears,  therefore,  that  the  results  of  tuberculous  infection 
are  dependent  partly  upon  the  local  effects  of  the  bacillus  in  the 
production  of  a  specific  avascular  granulation  tissue,  partly  upon 
the  tuberculous  poison.  Caseation  occurs  in  both  instances  al- 
though in  the  less  toxic  or  exhausted  infections  maturation  of  the 
tuberculous  granulation  tissue  to  an  unhealthy  scar  is  the  common 
ending. 

It  has  already  been  mentioned  that,  particularly  in  later  stages, 
additional  mixed  infection  with  other,  usually  pus-producing  or- 


CHANGES  IN  LOCAL  CELL  RELATIONS          239 

ganisms,  is  common  (streptococci,  pneumococci,  influenza  bacilli, 
even  putrefactive  bacteria).  They  add  materially  to  the  softening 
ulceration  and  further  inflammation  of  tuberculous  organs. 

2.  Syphilitic  Inflammations.  The  inflammatory  lesions  which 
are  excited  by  the  spirocheta  pallida  differ  somewhat  in  different 
stages  of  the  disease.  The  so-called  primary  lesion  (chancre)  is 
made  up  of  a  mononuclear  exudate,  rich  in  plasma  cells,  intimately 
connected  with  blood  vessels  in  perivascular  foci.  Connective-tis- 
sue fibrils  swell  and  appear  rigid.  Vessels  themselves  are  involved 
early  by  proliferation  of  their  endothelial  linings,  leading  to 
thickening  and  hyaline  fusion  of  the  vessel  wall.  Spirochetes  may 
be  demonstrated  in  the  endothelial  cells  of  small  vessels  and  in  peri- 
vascular  lymph  spaces.  Proliferation  of  connective  tissue  occurs 
early.  This  forms  fibrils  and  finally  a  retracting  scar.  Late  syphilitic 
inflammations  lead  either  to  nodular,  localized,  elastic  (rubber-like) 
inflammatory  growths,  known  as  gummata,  or  appear  as  peri- 
vascular  infiltrations.  They  are  essentially  of  similar  structure. 
They  consist  of  a  granulation  tissue,  rich  in  plasma  cells,  epithe- 
lioid  cells  and  fibroplasts,  occasionally  with  Langhans'  giant  cells, 
and  always  stand  in  intimate  connection  with  blood  vessels  (peri- 
vascular  cell  infiltrations).  These  vessels  show  generally  intimal 
proliferation  and  fibrous  thickening  of  their  adventitial  coats. 
The  syphilitic  granulation  tissue  is  further  characterized  by  a 
limited  number  of  new  embryonic  blood  capillaries.  In  larger 
arteries  the  adventitia  is  primarily  involved  by  perivascular  cell 
infiltrations  of  lymphocytes  and  plasma  cells,  later  with  epithelioid 
cells  and  fibroplasts  around  the  vasa  vasorum.  These  spread  in 
patchy  progress  to  the  muscular  media. 

Syphilitic  granulation  tissue  shows  a  tendency  to  fatty  necrosis 
(yellow  appearance),  but  necrosis  is  generally  later,  less  complete 
and  less  extensive  than  in  tuberculosis  evidently  because  the 
spirochete  is  of  low  toxicity  and  because  some  vascularization  of 
the  syphilitic  granulation  tissue  is  provided  for.  The  tendency 
is,  therefore,  more  towards  cicatrization.  Blood  vessels  remain 
permanently  thickened  and  narrowed. 

The  anatomical  and  histological  diagnosis  between  tuberculous 
and  syphilitic  granulation  tissue  is  not  always  easy  and  sometimes 


240  GENERAL  PATHOLOGY 

impossible  without  demonstration  of  the  etiological  factor.  Gen- 
erally speaking  it  may  be  made  on  the  following  grounds:  (i) 
In  tuberculosis  caseation  is  greater  and  early,  in  the  gumma  a 
fatty  degeneration  is  the  rule,  giving  the  tissues  a  yellowish,  soft, 
but  not  cheesy  consistency.  (2)  Connective  tissue  formation  and 
scar  replacement  with  retraction  of  surrounding  parts  is  generally 
greater  in  the  gumma  than  in  the  tubercle.  (3)  Fatty  necrosis  and 
breaking  down  of  tissues  occurs  later  and  is  less  complete  in  the 
syphilitic  granuloma.  (4)  Vascular  involvement  (perivascular  cell 
infiltrations  and  blood-vessel  thickening  and  narrowing)  is  more 
pronounced  in  syphilis  than  in  tuberculosis.  (5)  The  syphilitic 
granulation  tissue  is  somewhat  vascularized  by  newly  formed  capil- 
laries, the  tubercle  never.  Faint  structural  outlines  are  often  still 
discernible  in  the  softening  gumma,  not  in  the  rapidly  caseating 
tubercle.  It  is  never  safe  to  depend  upon  one  point  alone,  only 
the  presence  of  a  number  of  these  factors,  carefully  considered, 
allow  reasonable  diagnosis. 

Both  tuberculous  and  syphilitic  granulomata  lead  sometimes  to 
extensive  epithelial  proliferation  in  infected  organs,  especially  in 
the  skin  (see  also  Blastomycosis).  The  epidermis  may  grow  down 
into  the  inflamed  foci  but  remains  in  contact  and  isolated  parts  do 
not  grow  further  but  disintegrate.  This  latter  point  is  important  as 
a  differentiation  from  early  cancerous  tumors.  But  there  is  no  doubt 
that  such  lesions  may  gradually  develop  into  cancer,  i.e.,  acquire 
independent  epithelial  growth  (see  under  Tumors). 

3.  Leprous  inflammations  occur  in  nodular  or  ulcerative  form. 
Nodules  are  mustard  seed  to  plum  sized,  globular,  broad  based, 
yellowish  or  bluish.  Microscopically  these  show  infiltrations  with 
mononuclear  (leucocytoid)  cells  often  in  more  or  less  perivascular 
arrangement  and  characteristic  large  vesicular  cells  which  contain 
lepra  bacilli.  But  bacilli  also  lie  extracellular.  These  infiltrations 
completely  destroy  the  tissue  they  occupy.  Regenerative  changes 
are  more  limited  and  irregular  than  in  either  tuberculosis  or  syph- 
ilis.  Secondary  infection   with   pyogenic   micro-organisms  is  not 
uncommon. 

4.  Actinomycotic  inflammations  present  purulent  foci  leading  to 
abscesses  and  ulcerations.  In  man  and  cattle  occur,  however,  at 


CHANGES  IN  LOCAL  CELL  RELATIONS          241 

times  nodular,  tumor-like  growths  (brain,  rarely  in  liver).  The 
ray  fungus  leads  at  first  to  a  localized  inflammatory  area  consisting 
of  pus  cells,  associated  later  with  granulomatous  cell  infiltrations 
of  epithelioid  and  giant  cells.  These  carry  a  small  number  of  newly 
formed  blood-vessels,  but  appear  yellowish  and  are  soft  from  the 
start.  As  the  lesion  progresses,  unhealthy,  fatty  scar  tissue  is 
produced  at  the  periphery  of  the  actinomycotic  nodule.  The  center 
exhibits  the  characteristic  radiating,  often  club-shaped  filamentous 
convolutions.  The  tendency  of  the  lesion  is  to  cicatrize  in  parts 
while  others  progress  by  purulent  fusion  and  sinus  formation. 
These  sinuses  extend  towards,  and  frequently  break  through,  the 
surface. 

5.  Glanders  produces  partly  diffuse,   partly  nodular  purulent 
or    ulcerating   foci.    In   acute   glanders  the   purulent    character 
predominates.  The  fixed  tissue  necroses  to  a  finely  granular  detritus. 
In  chronic  glanders  appear  epithelioid  and  large  multinuclear  cells 
but  not  typical  giant  cells.  Horses  sometimes  show  a  stronger 
cicatrization  around  the  nodules,  especially  in  the  lungs. 

6.  Rbinoscleroma  leads  to  inflammatory,  hard,  bluish  nodules  in 
the  upper  respiratory  passages,  especially  in  the  nose.  These  have 
only  little  tendency  to  disintegrate.   Microscopically  they  are 
composed  mostly  of  perivascular  plasma  cells  in  atrophic  fixed 
connective  tissue,  while  other  parts  show  swelling,  thickening 
and  fusion  of  fibers.  Then  occur  hyaline,  hydropsical  cells  contain- 
ing the  bacilli.  The  surface  epithelium  thickens  over  these  areas. 

7.  Blastomycosis,  a  granulomatous,  ulcerative  and  sometimes 
purulent  lesion  of  skin,  gut  and  lungs  must  be  mentioned  finally. 
It  is  excited  by  a  pathogenic  yeast,  the  blastomyces.  Generally, 
yeasts  are  harmless  and  saprophyte.  They  are  round  or  oval,  clear, 
sometimes  capsulated  cells  which  propagate  by  budding.  The 
pathogenic  blastomyces  probably  enter  through  the  mouth  with 
food.  The  blastomycotic  lesions  are  typically  granulomatous  and 
often  also  excite  epithelial  tissues,  especially  in  the  skin,  the  epi- 
dermis,  to  more  or  less  active  proliferation  so  that  pictures  of 
early  cancer  may  be  simulated.  But  similar  pictures  occur  in 
tuberculosis  and  syphilis  (see  above).  Characteristic  yeast  cells 
are  generally  to  be  seen  in  the  lesions. 

16 


242  GENERAL  PATHOLOGY 

8.  Granulomata  of  Unknown  or  Uncertain  Etiology.  Besides  the 
granulomata  so  far  considered  which  may  be  traced  to  known 
micro-organisms  and  are  of  more  or  less  characteristic  morphology, 
there  occur  a  number  of  others  with  predilection  for  the  lymphoid 
system,  which  cannot  be  traced  to  a  specific  cause  and  are  of 
variable  anatomical  and  histological  appearance.  Of  these  the 
so-called  "  Hodgkin's  disease,"  better  lymphogranulomatosis  (not 
pseudoleucemia),  stands  out  as  an  anatomical  entity.  It  consists 
of  increasing  and  progressing  lymph  gland  swelling,  generally 
first  in  the  neck,  followed  by  mediastinal  and  other  glands. 
They  form,  often,  very  large,  deforming  packets  in  which, 
however,  the  individual  glands  remain  isolated  and  discrete. 
Histologically  the  lesion  shows  glandular  obliteration  and  re- 
placement by  many  polymorphous  cells  of  granulation  tissue 
(Lymphoid  cells,  plasma  cells,  giant  and  epithelioid  cells).  Con- 
spicuous are  eosinophiles.  Tendency  to  necrosis  exists  but  is 
limited  and  generally  quite  incomplete.  Definite  capillary  buds 
and  vessels  are  not  carried  by  this  granulation  tissue.  Cicatrization 
occurs  in  parts. 

Hodgkin's  disease  must  not  be  confounded  with  unusual  cases  of 
productive  lymph  gland  tuberculosis  (Sternberg)  in  which  a  similar 
gross  picture  is  produced  but  in  which  the  histological  character 
is  that  of  an  active  proliferation  of  more  or  less  uniform  large 
epit;helioid  or  spindle-shaped  cells  which  replace  the  gland  struc- 
ture. Regressive  changes  are  present,  but  are  often  very  slight,  so  that 
differentiation  from  a  true  tumor  may  be  difficult.  In  Hodgkin's 
disease  the  polymorphous  character  of  the  cells,  tendency  to  re- 
gression and  cicatrization,  however,  usually  allow  histological 
diagnosis.  Hodgkin's  disease  and  Sternberg's  lymph  gland  tu- 
berculosis involve  sooner  or  later  parenchymatous  organs  (spleen, 
liver,  etc.)  in  nodular  growths  which  closely  simulate  tumor 
metastases.  Transitional  growths  between  these  inflammatory 
granulomata  and  true  tumors  have  been  described. 

The  origin  and  cause  of  Hodgkin's  disease  is  quite  uncertain. 
From  time  to  time  bacteria  have  been  isolated  (especially  diph- 
theroids)  which,  however,  are  probably  only  accidental  findings. 
Whether  it  is  of  uniform,  specific  etiology  is  doubtful  as  many 


CHANGES  IN  LOCAL  CELL  RELATIONS          243 

attenuated  infections  may  produce  similar  pictures.  In  Sternberg's 
lesions  tubercle  bacilli  have  been  demonstrated. 

The  skin  is  not  infrequently  the  seat  of  similar  granulomata  or 
ulcerations  of  uncertain  etiology. 

Detailed  description  of  these  lesions  is  properly  the  field  of 
special  pathology. 


II.    TUMORS 

Originally  tumor  meant  swelling  of  any  sort.  Later,  the  term  was 
confined  to  all  kinds  of  inflammatory  and  non-inflammatory  new 
growths.  Since  Virchow's  time  the  conception  of  tumor  is  restricted 
to  the  autonomous,  independent  growths  of  tissues.  While  all  other 
growths,  i.e.,  hypertrophy,  regeneration,  productive  inflammations, 
are  in  fundamental  character  regulated,  prescribed  by  or  at  least 
adapted  to,  and  directly  dependent  upon,  their  immediate  en- 
vironment, the  tumor  is  independent  from  its  origin  and  incip- 
iency.  The  tumor  is  a  new  creation,  an  entity  of  its  own,  arising 
apparently  spontaneously  and  not  as  the  direct  result  of  definitely 
recognizable  external  irritations.  The  tumor  is  rather  the  result 
of  a  combination  of  circumstances,  some  remote,  some  recent,  which 
inaugurate  independent  cell  prolification. 

Independence  is-,  therefore,  the  most  outstanding  attribute  of  a 
tumor.  While  all  tumors  resemble  more  or  less  normal  tissues  or 
organs,  they  are  of  a  lower  cell  grade  and  type.  This  deviation  from 
physiological  conditions  may  be  only  slight,  (homologous  tumors) 
or  great  enough  to  lose  all  resemblance  to  the  mother  tissue, 
(heterologous  tumors).  The  first  are  more  mature,  differentiated 
in  type,  the  second  embryonic,  less  differentiated. 

It  is,  however,  by  no  means  easy  to  draw  a  sharp  line  of  division 
between  tumors  and  other  growths,  for  excessive  pathological  re- 
generation or  inflammatory  hyperplasias  may  at  times  resemble  or 
gradually  assume  the  manners  of  true  tumors.  The  exact  time  or 
the  moment  when  pathological  hyperplasias  take  on  the  character 
of  tumors  is  impossible  to  decide.  Here  the  accompanying  circum- 
stances of  the  growth  must  be  considered  with  equal  care  to  arrive 
at  a  probable  diagnosis. 


244  GENERAL  PATHOLOGY 

Tumors  must,  furthermore,  be  separated  from  developmental 
malformations  or  faulty,  developmental  tissue  organization.  The 
first  of  these  are,  according  to  Albrecht,  better  termed  hamarto- 
mata,  (ajuaprta  =  error)  the  second,  choristomata  (x^pto-ros  = 
separated).  These  are  stationary,  but  tumors  may  arise  from  such 
developmental,  uncoordinated  anomalies  in  structure. 

i.  GENERAL  CHARACTERISTICS.  Tumors  are  either  circumscribed, 
and  nodular,  or  diffuse  and  infiltrating,  often  both.  On  the  surface, 
they  may  project  as  tuberosities  or  fungi  or  are  attached  by 
a  pedicle  (polyp).  Every  tumor  is  made  up  of  the  essential  tumor 
parenchyma  and  a  stroma.  Some  consist  almost  entirely  of  their 
characteristic  parenchyma  (histoid  tumor) ;  others  show  a  definite 
structural  arrangement  in  parenchyma  cell  and  interstitial  stroma. 
These  resemble  in  a  degree  organ  construction  (organoid  tumor). 

The  parenchyma  of  a  tumor  consists  of  specific  tumor  cells. 
These  resemble  in  greater  or  lesser  degree  the  original  mother  tissue 
from  which  the  tumor  springs.  Even  in  those  tumors  which  bear  the 
closest  resemblance  to  their  mother  tissue,  the  parenchyma  carries 
certain  characteristics  of  its  own.  Often  the  morphological  relation 
of  nuclei  and  cytoplasm  is  disturbed.  Generally,  nuclei  in  tumor 
cells  are  absolutely  and  relatively  larger  (very  rarely  smaller)  than 
in  the  physiological  tissue.  The  differentiation  of  cells  is  less  com- 
plete and  uniform.  New  cells  appear  more  supple  and  even  the 
finished  products  are  more  or  less  atypical  in  appearance  and 
arrangement.  These  characteristics  are,  of  course,  more  marked  in 
embryonic  tumor  types,  which  never  reach  maturity.  In  them  nu- 
cleus-plasma relations,  chromatin  production  in  the  nucleus,  and 
differentiation  of  the  cytoplasm  are  correspondingly  disturbed. 

Tumor  cells  may  retain  at  least  some  of  the  functions  of  the 
mother  tissue  from  which  they  take  origin.  Some  may  thus  secrete 
mucus,  colloid  matter,  bile,  etc.  The  proliferation  of  tumor  cells 
occurs  by  mitosis  and  amitosis.  Pathological  forms  of  division  are 
frequently  encountered  in  the  more  rapidly  proliferating  (malig- 
nant) tumors.  Irregular  cell  division  or  fusion  leads  to  tumor  giant 
cells  and  syncytium. 

The  stroma  of  a  tumor  is  made  up  of  connective  tissue,  which  is 
originally  derived  from  that  of  the  mother  tissue.  It  is  either  fibrous 


CHANGES  IN  LOCAL  CELL  RELATIONS          245 

connective  tissue  or  one  of  its  derivatives.  Some  tumors  exhibit  a 
definite,  quantitative  relation  between  parenchyma  and  stroma, 
and  this  is  preserved  throughout  the  growth;  in  others  this  varies. 
Sometimes  the  parenchyma  cells  overgrow  and  crowd  the  stroma 
(medullary  tumors);  sometimes  the  stroma  becomes  excessive 
and  the  tumor  cells  are  confined  to  small  narrow  islands  (cancer 
nests  in  scirrhus  cancer). 

The  stroma  carries  the  nutrient  blood  and  lymph  vessels  of 
the  tumor.  Some  have  a  very  abundant  supply,  others  are  poorly 
provided  for  and,  therefore,  easily  undergo  regression.  A  tumor 
once  formed  grows  by  proliferation  of  its  own  elements  alone. 
Neighboring  cells  may  be  replaced,  brought  to  atrophy,  but  are 
never  converted  into  tumor  cells.  Most  tumors  seem  to  take  their 
origin  from  small,  localized  areas  and  by  expansion  or  infiltration 
replace  the  normal  tissue.  It  seems  that  in  some  instances  a  multi- 
ple origin  is  possible.  The  growth  of  a  tumor  is  always  destructive, 
except  when  it  is  situated  on  the  surface,  but  the  tempo  of  the 
growth  varies  tremendously.  Some,  of  embryonic  character,  grow 
from  the  start  without  any  restraint,  until  the  carrier  dies  (ma- 
lignant). But  even  in  these  malignant  types  there  exist  many 
individual  variations.  Again,  tumors  approaching  a  greater  phys- 
iological organization  or  coming  from  certain  tissues  (fat,  glia), 
may  grow  very  slowly,  years,  even  decades. 

Every  tumor  is  -originally  a  local  disease,  although  at  times  of 
multiple  origin.  Some  tumors  retain  their  local  confinement 
throughout;  others,  especially  the  rapidly  growing,  young,  cellular 
growths,  produce,  sooner  or  later,  similar  tumors  in  other,  often 
distant,  parts  of  the  body.  This  occurs  by  transportation  of  free 
tumor  cells  which  have  broken  into  the  blood  and  lymph  streams. 
They  settle  in  a  suitable  environment  and  reproduce  their  own 
kind,  that  is,  a  secondary  growth  resembling  the  original.  This  is 
metastasis. 

2.  METASTASIS.  Metastases  in  tumors  are  secondary  growths 
of  the  same  character  as  the  original,  but  at  distant  points  and  not 
connected  with  the  original  or  with  each  other.  Metastases  may 
occur  in  the  neighborhood  (regional)  or  be  far  removed.  They  may 
be  solitary  and  isolated,  or  multiple  and  extensive.  In  every  instance 


246  GENERAL  PATHOLOGY 

they  find  their  origin  in  tumor  cells  transported  by  lymph  or  blood 
streams. 

But  transportation  and  fixation  of  cells  in  foreign  tissues  do  not 
constitute  metastasis,  for  cells  may  be  destroyed  after  their  arrest. 
The  conception  of  metastasis  requires,  therefore,  not  only  trans- 
portation and  fixation  of  tumor  cells,  but  growth  and  develop- 
ment to  a  tissue,  similar  to  the  original,  with  power  to  replace  the 
physiological  tissue  in  which  it  resides.  Thus  the  problem  of  meta- 
stasis does  not  rest  in  cell  transportation  and  fixation,  but  in  the 
tumor  character  after  these  have  taken  place. 

Metastases  are  characteristic  of  rapidly  growing,  cellular,  em- 
bryonic tumors.  Their  active,  infiltrating  manner  of  growth  easily 
allows  dislocation  of  cells  and  entrance  in  considerable  number  into 
the  circulation.  These  travel  with  the  current,  but  sometimes  by 
their  own  ameboid  motion  (so-called  chemiotaxis)  against  it.  But 
it  is  now  recognized  that  even  slow  growing,  inactive,  so-called 
benign  tumors  may  occasionally  be  followed  by  secondary  growths 
in  other  organs,  while,  on  the  other  hand,  some  cellular,  embryonic, 
even  locally  destructive  tumors  may  remain  without  metastatic 
extensions.  Thus,  some  tumors  of  well-developed,  typical  fibrous, 
myxoid  and  muscle  tissues,  of  cartilage,  blood  vessels  (angiomata) 
and  of  well-developed  thyroid  tissue  may  at  times  infiltrate  and  me- 
tastasize,  while  cancer  of  the  sexual  organs  (uterus,  ovary),  of  the 
liver,  sarcomata  of  fascia,  periosteum  (epulis),  cellular  tumors  from 
neuroglia,  endotheliomata  of  the  dura  mater  and  tumor-like 
embryonic  remains  or  faulty  tissue  mixtures  (hamartomata  and 
choristorriata,  see  above)  very  rarely  lead  to  metastases.  Into  the 
formation  of  metastases  enter,  therefore,  a  number  of  contribu- 
tory factors,  some  of  which  are  more  or  less  known,  others  quite 
obscure. 

The  following  contributory  causes  may  be  recognized : 

i.  The  quantity  and  quality  of  the  tumor  cells  which  are  thrown 
into  either  blood  or  lymph  circulation.  In  these  respects  tumor  cells 
behave  like  invading  parasites.  When  ordinarily  a  small  number 
enter  and  are  moved  along  the  lymph  stream,  they  are  anchored 
by  certain  tissues  more  readily  than  by  others.  On  the  other  hand, 
when  there  occurs  a  direct  extensive  break  into  the  blood  circula- 


CHANGES  IN  LOCAL  CELL  RELATIONS          247 

tion,  elective  action  and  localization  do  not  occur  and  general 
dissemination  results.  Certain  strains  of  tumor  cells  appear  to 
have  stronger  power  of  growth  than  others. 

2.  Inflammation  and  degeneration  of  a  tissue  often  seem  to  pre- 
pare the  soil  for  tumor  metastases  by  eliminating  physiological 
tissue  resistance  and  antagonism  to  foreign  cells.  This  occurs 
frequently  in  the  neighborhood  of  tumors,  especially  in  the  region- 
ary  lymph  glands  into  which  tumor  products  drain  concentrated 
products.  Therefore,  it  is  important  that  not  all  enlarged  glands 
in  the  immediate  view  of  a  tumor  are  absolute  evidence  of  metas- 
tases. They  may  be  simply  inflammatory  and  either  continue  so 
or  later  be  overcome  by  tumor  involvement. 

3.  Selection.  Some  tumors  show  a  greater  tendency  to  metastases 
on  certain  tissue  soils  than  on  others.  Lymphosarcoma  settles  with 
predilection   in  other  lymphoid  tissue.  Glandular  ectodermal  or 
entodermal  cancers  are  likely  to  select  other  glandular  organs 
of  the  same  derivation.  There   is  some  evidence  to  show  that 
close  biogenetic  (embryonic)  relation  of  tumor  cells  to  a  tissue 
soil  is  of  importance.  Thus  types  of  tumor  cells   derived  from 
an  embryonic  layer  seem  to  grow  more  readily  in  the  environment 
of  organs  or  tissues  which  are  derived  from  the  same  layer  of  the 
blastoderm. 

Besides  these  three  factors  there  may  be  others  but  of  those  we 
know  as  yet  nothing. l  It  seems  that  certain  organs  like  the  spleen  and 
kidney  are  much  less  liable  to  metastases  than  others,  although 
the  mechanical  arrangement  of  their  parts  renders  them  particu- 
larly open  to  retention  of  foreign  cells.  Generally  speaking,  it  does 
not  appear  that  these  mechanical  points  are  of  great  issue  in 
localization  of  metastases  anywhere,  except  possibly,  when  over- 
whelming numbers  of  cells  are  arrested. 

The  manner  of  metastatic  progress  in  lymph  and  blood  vessels 
is  interesting.  Sometimes  cells  are  floated  away  in  the  stream;  more 
common  is  a  primary  sort  of  staircase  ascent  in  lymph  vessels. 
Here  tumor  cells  attach  themselves  to  the  lining  endothelial  cells 
of  the  lymphatic,  bring  them  to  atrophy  and  thus  line  and  climb 

furious,  but  quite  obscure,  is  the  occasional  latency  of  growth  in  tumor  cells 
in  a  foreign  tissue.  Thus,  years  may  escape  until  metastases  make  an  appear- 
ance after  removal  of  a  primary  tumor. 


248  GENERAL  PATHOLOGY 

along  the  lymph  vessel  wall.  By  proliferation  they  gradually  fill 
the  lumen  in  their  advance. 

Metastasis  by  blood  vessels  occurs  by  penetration  of  tumor  cells 
into  capillaries  and  veins.  They  then  form  a  tumor  embolus. 
Growth  proceeds  by  adherence  to  the  vessel  wall  and  perforation 
to  the  outside,  or  first,  by  growth  within  the  vessel  lumen.  Favorable 
is,  of  course,  the  thinner  wall  and  slower  current  under  relatively 
low  pressure  in  venules. 

3.  GENERAL  HISTOLOGY  AND  DIAGNOSIS  OF  TUMORS.     It  has 
already  been  stated  that  an  accurate,  strict  distinction  between 
tumors  and  other  hyperplastic  conditions   is   not  always  easy. 
Hypertrophy  of  whole  organs  is  more  easily  distinguished,  for  here 
the  manner  of  growth  and  arrangement  of  new  parts  conform 
strictly  to  the  physiological  prototype  to  which  it  fits  itself  anatom- 
ically and  functionally.  But  slowly  progressing  pioductive  inflam- 
mations, especially  infective  granulomata  may,  on  account  of  their 
localized,  nodular  manner  of  growth,  their  metastases-Iike  gen- 
eralization,  and   even   their   microscopic   appearance,    introduce 
diagnostic  difficulties.  As  a  cardinal  point  of  distinction  it  should 
be  remembered  that  true  tumor  growth  is  characterized  by  uni- 
formity of  cell  type  and  arrangement  and  the  rapid  and  uniform 
cell  differentiation  to  one  point.  This  is  noticeable  even  in  young 
and  in  advancing  tumors.   When   mixtures  of  tissues  occur   in 
tumors,  the  combination  is  never  so  diffuse  and  irregular  as  that 
of  the  various  cell  types  in  inflammatory  growths,  but  cells  and 
tissues  arrange  themselves  into  territories. 

Inflammatory  tissues  are,  except  in  unusual  border  line  cases, 
varied,  of  polymorphous  cell  character,  and  of  different  cell  type. 
They  exhibit  uneven  variations  in  cell  differentiation  and  progress 
by  leaps  and  bounds.  In  them  also  the  initial  tissue  changes  differ 
widely  from  the  end-product. 

4.  GENERAL  CONSTITUTIONAL  EFFECTS  OF  TUMORS.     Tumors 
are  divided  according  to  their  biological  behavior  into  local,  so- 
called  benign,   growths,   and  generalizing,   infiltrating,    so-called 
malignant  growths. 

The  benign  tumors  are  generally  of  mature  or  approximately 
mature  tissue  type,  solitary  or  occasionally  multiple,  and  grow 


CHANGES  IN  LOCAL  CELL  RELATIONS          249 

slowly  and  by  expansion.  There  is  as  a  rule  no  tendency  to  metas- 
tasize  or  grow  diffusely  into  the  surrounding  tissues,  but  they 
frequently  are  encapsulated.  They  gradually,  however,  replace 
neighboring  organs  by  pressure  atrophy,  may  grow  to  large  size 
and  by  pressure  and  mechanical  interference  may  become  dan- 
gerous in  the  vicinity  of  vital  organs.  General  constitutional  effects 
are  lacking.  But  tempo  of  growth  and  increasing  immaturity  of 
tissue  elements  may  occur  at  any  time  and  gradually,  impercep- 
tibly, lead  to  characters  of  malignancy. 

Thus  no  sharp  line  of  demarcation  separates  benign,  mature, 
from  malignant,  immature  growths  and  it  is  often  difficult,  even 
impossible,  to  decide  from  the  histological  picture  alone  whether  a 
tumor  still  belongs  to  the  former  class  or  has  already  crossed  the  line 
to  the  latter.  For,  after  all,  the  biological  behavior  and  attitude  of  a 
tumor  are  not  absolutely  reflected,  especially  in  transitional  types, 
by  their  morphology.  The  histological  morphology  is  only  to  be 
trusted  in  the  typical  cases,  in  others,  manner  of  origin,  course,  gross 
appearances,  etc.,  must  be  carefully  considered  as  part  of  the  evi- 
dence. Moreover,  it  has  already  been  mentioned  that  some  tumors 
of  mature  tissue  may  generalize,  while  at  times  those  of  embryonic 
constitution  may  remain  local  and,  after  excision,  do  not  recur. 

Of  great  interest  and  very  impressive  are  the  constitutional 
effects  of  rapidly  growing,  clinically  malignant  tumors.  They 
produce  pictures  which  resemble  either  severe  anemias  (hemor- 
rhages from  vascular  tumors)  or  starvation  (emaciation)  or  a  char- 
acteristic chronic  intoxication  known  as  tumor  cachexia.  Some  of 
the  tumor  effects  are  undoubtedly  due  to  gross  interference  with 
nutrition  (stenosis  in  a  part  of  the  gastro-intestinal  tract),  in  others 
to  infections,  ulcerations,  or  putrid  softening  of  the  tumor  itself. 

Then  also,  extensive  metastases  interfere  with  normal  meta- 
bolic functions  and  relations.  By  tumor  cachexia  in  the  strict  sense 
something  different  is  meant.  It  is  apparently  a  chronic  intoxica- 
tion which  has  its  origin  in  metabolic  tumor  products  (secretion, 
excretion,  ferments).  Thus  blood  and  urine  of  cancer  patients  have 
been  found  to  contain  hemolytic  substances.  This  true  tumor  ca- 
chexia is  more  frequent  in  cancer  (glandular  tumor)  than  in  other 
malignant  growths  (sarcomata)  in  which  hemorrhages,  softening, 
etc.,  are  more  generally  found. 


250  GENERAL  PATHOLOGY 

It  is  interesting  that  tumors  of  certain  derivations  display  func- 
tions imitating  those  of  the  mother  tissue  (hormone  action).  For 
example,  chorioepithelioma,  a  malignant  tumor  of  the  fetal 
chorion,  may  occasionally  produce  late  metastasis  in  the  lung  (one 
year  after  pregnancy).  In  these  cases  persistence  of  decidua  and 
milk  production  in  the  breasts  have  been  observed.  Thus,  also, 
tumors  of  the  ovary,  testicle  and  hypophysis  may  lead  to  abnorm- 
ally early  sexual  maturity. 

Spontaneous  healing  or  regression  in  tumors  is  generally  only 
partial  through  ulceration,  softening  and  cicatrization.  In  ma- 
lignant tumors  in  man  it  practically  never  leads  to  destruction  or 
loss  of  the  whole  growth  which  goes  on  in  some  parts  as  others  dis- 
integrate. There  are  only  a  very  few  not  well  understood  cases  in 
which  an  apparently  malignant  growth  suddenly  halted  and  dis- 
appeared. In  one  instance  (Orth)  the  patient  died  several  years 
afterwards  from  a  metastasis,  although  the  original  adenocar- 
cinoma  did  not  reappear.  Regression  of  tumors  in  mice,  however, 
seems  more  common. 

5.  CLASSIFICATION  OF  TUMORS.  It  has  always  been  a  difficult 
problem  to  classify  tumors,  principally  because  they  may  deviate 
in  structure  and  cell  character  amongst  members  of  the  same  kind 
and  from  the  mother  tissue.  Attempts  have  been  made  to  discard 
classification  based  on  histological  appearances  entirely,  and  to 
substitute  classification  based  on  embryogenetic  derivation.  This, 
however,  has  only  introduced  new  difficulties,  because  it  obliges  us 
to  separate,  and  distinguish  between,  types  which  in  common  mor- 
phological character,  biological  behavior,  and  by  long  usage  nat- 
urally fall  into  one  category  of  tumors,  irrespective  of  their  origin. 
For  example,  cancers  of  the  kidney  and  uterus  would  have  to  be 
separated  from  other  cancers  as  being  of  mesodermal  origin,  and  the 
gliomata  would  have  to  be  regarded  as  epithelial  in  character, 
although  the  appearance  and  function  of  the  glia  in  the  fully 
developed  organism  are  those  of  a  stroma  and  gliomata  grow  and 
behave  like  other  tumors  from  stroma. 

It  seems  best,  then,  to  retain  a  classification  which  depends  upon 
the  histological  appearance,  manner  of  growth,  arrangement  and 
biological  behavior  of  the  tumor  itself,  irrespective  of  origin  and 


CHANGES  IN  LOCAL  CELL  RELATIONS          251 

embryogenetic  relations.  In  a  great  many  tumors  these  fall  to- 
gether with  appearance  and  manner  of  growth,  in  some  they  are 
still  uncertain  (melanomata)  or  so  removed  from  the  tumor  itself 
that  embryogenesis  cannot  serve,  but  only  confuse,  in  classification. 

CLASSIFICATION   OF   TUMORS 

I.  Histoid  Tumors.     (Tumors  consisting  of  one  or  several  tissues.) 

A,  Mature  differentiated  and  stationary  types. 

(a)  Connective  tissue  derivatives:  (i)  fibroma,  (2)  myxo- 
ma,  (3)  lipoma,  (4)  chondroma  (chordoma),  (5) 
osteoma. 

(6)  Lymphoid  tissue  derivatives:  lymphoma. 

(c)  Myeloid  tissue  derivatives:  myeloma. 

(d)  Pigmented  tumors:  melanoma. 

(e)  Muscle  tissue  derivatives:  myoma. 

(/)  Nervous  tissue  derivatives:  i.  glioma;  2.  neuroma. 

B.  Immature,  undifferentiated,  disseminating  types. 

(a  to  /)  Sarcomata. 

II.  Organoid    Tumors.     (Tumors    consisting    of    an    epithelial 

parenchyma  and  a  stroma  simulating  organ  construc- 
tion.) 

A.  Mature,  differentiated  and  stationary  types: 

(a)  Papilloma. 
(6)  Adenoma, 
(c)  Cystoma. 

B.  Immature,  undifferentiated,  disseminating  types: 

(a  to  c)  Carcinomata. 

III.  Endotheliomata. 

A.  Histoid  types  (mature  or  immature),  angiomata  (vascular 

and  lymphatic.) 

B.  Organoid  types:  from  lining  endothelium  of  serous  mem- 

branes. 

IV.  Mixed  Embryonic  Tumors  (of  developmental  origin.) 

A.  Teratoid  growths. 

B.  Teratomata. 

C.  Embryomata. 


252  GENERAL  PATHOLOGY 

I.  HISTOID  TUMORS.  A.  MATURE  DIFFERENTIATED  AND  STATION- 
ARY TYPES,  (a)  Connective  tissue  derivatives: 

i.  Fibroma.  This  is  a  tumor  whose  parenchyma  is  made  up  of 
fibroplasts  in  advanced  stage  of  differentiation  with  fibrils  and 
fibers.  They  carry  a  variable  number  of  blood  and  lymph  vessels. 
Grossly  these  tumors  are  as  a  rule  well  circumscribed  and  occur 
in  organs  or  on  their  surface  in  the  form  of  nodes,  tuberosities  or 
polyps.  Their  manner  of  growth  is  expansive,  not  infiltrative,  slow 
and  clinically  benign  without  metastases. 

There  exist  two  main  types  of  this  tumor;  the  fibroma  durum, 
(hard  fibroma)  of  closely  packed  thick  fibers,  poor  in  cells  and  nu- 
clei, the  old  desmoid.  The  second  is  the  fibroma  molle  (soft  fibro- 
ma), which  consists  of  loose,  fine  fibrillar,  interwoven  connective 
tissue  threads,  rich  in  cells  and  nuclei  which  rest  in  a  gelatinous  or 
edematous  ground  substance  which  separates  aggregates  of  cells. 
These  cell  clusters  are  frequently  grouped  around  blood  vessels. 

Hard  fibromata  are  tendinous,  white,  often  shining,  pearly  on 
section  and  encapsulated.  The  growth  shows  closely  packed  thick 
bands  and  coils  of  connective  tissue.  They  are  found  wherever 
fibrous  tissue  exists,  most  frequently,  however,  in  the  skin,  muscles, 
tendons,  fascia,  and  periosteum.  A  special  form  of  fibroma  is  the 
"keloid."  This  takes  origin  from  cicatrices  (trauma)  by  irregular 
scar  overgrowth  and  thus  forms  nodes,  strands  and  even  plates 
projecting  from  the  seat  of  the  scar.  It  represents  a  tumor-like  over- 
growth of  the  cicatrix.  There  seems  to  exist  a  peculiar  individual 
predisposition  to  it  as  it  occasionally  makes  its  appearance  in  cases 
of  relatively  trivial  injuries,  for  example,  on  the  site  of  an  earring 
perforation.  For  similar  reasons  the  keloid  is  likely  to  recur  after 
removal. 

Soft  fibromata  are  whitish  or  reddish  (vascular),  somewhat 
transparent,  edematous  gelatinous  growths  in  the  form  of  nodes  or 
polyps.  We  find  microscopically  much  gelatinous  matrix  which 
separates  cells  and  cell  aggregates.  The  cells,  moreover,  do  not 
reach  entire  full  differentiation.  Fibers  are  not  produced,  fibrils 
sparingly,  and  cells  remain  at  the  stage  of  the  spindle.  Instead,  they 
furnish  an  excessive  amount  of  gelatinous  intercellular  substance 
with  affinity  for  acid  stains.  The  tumors  deviate  then  from  the 


CHANGES  IN  LOCAL  CELL  RELATIONS          253 

normal  connective  tissue  to  greater  or  lesser  extent  and  they  easily 
lose  further  in  differentiation,  become  more  and  more  immature 
and  assume  a  sarcomatous  character.  Even  when  they  do  not,  they 
are  apt  to  recur  and  always  remain  suspkious  in  their  future  be- 
havior. They  spring  most  frequently  from  cutaneous,  subserous 
and  mucoid  connective  tissue  and  around  nerves. 

Of  note  is  the  occasional  multiple  occurrence  of  fibromata  over  the 
whole  skin  in  the  form  of  soft  nodes  (fibroma  molluscum)  and  they 
are  often  in  intimate  connection  with  nerves,  taking  their  origin 
from  perineurium  and  endoneurium  (false  neuromata).  The  con- 
dition is  at  times  congenital  and  occurs  with  pigmented  moles  (see 
later).  It  may  follow  the  course  of  nerves,  forming  wreath-like 
thickenings  or  plexiform  arrangements. 

The  vascularity  of  fibromata  varies  tremendously.  Those  rich  in 
blood  vessels  are  sometimes  spoken  of  as  fibroma  telangiectaticum. 
Others  are  rich  in  lymph  channels  (fibroma  lymphangiectaticum). 

In  the  poorly  nourished  more  or  less  a  vascular  fibromata  hyaline 
degeneration  of  fibrils  followed  by  calcification  is  frequent.  Trans- 
formation into  an  osteoid  or  true  osseous  tissue  may  then  be  noted 
in  them.  Occasionally  they  undergo  mucoid  degeneration  or  even 
become  myxomatous.  Fibromata  often  combine  with  other  con- 
nective tissue  tumors,  lipomata,  chondromata,  osteomata.  If  in 
these  mixed  tumors  the  fibrous  tissue  predominates,  the  other 
tumor  element  is  simply  added  as  a  qualifying  adjective,  for 
example,  fibroma  lipomatosum,  etc.  On  the  other  hand,  if  the 
contrary  prevails  the  phraseology  is  turned  around,  as  in  lipoma 
fibrosum,  etc. 

2.  Myxoma.  This  is  a  tumor  which  consists  from  its  incipiency 
entirely  of  a  vascularized  mucoid  tissue.  The  physiological  proto- 
type of  the  myxoma  is  Wharton's  jelly  of  the  umbilical  cord.  It 
must  not  be  confounded  with  partial  mucoid  changes  or  degenera- 
tions which  are  occasionally  found  in  other  connective  tissue 
tumors.  Myxomata  may,  however,  occur  in  combination  with  other 
types  of  connective  tissue  tumors,  especially  fibromata  and  lipo- 
mata (mixed  growths). 

They  are  localized,  nodular,  fungoid  or  polypoid,  grayish,  red- 
dish, soft  and  often  juicy  growths.  Histologically  they  are  charac- 


254  GENERAL  PATHOLOGY 

terized  by  delicate  spindle-shaped  stellate,  anastomizing  cells,  and 
round  cells  which  are  embedded  in  a  mucoid  matrix.  This  gives 
the  characteristic  micro-chemical  reaction  of  mucus  (stains  blue 
with  hematoxylin),  and  can  thus  be  differentiated  from  the  more 
irregularly  distributed  edematus  gelatinous  fluid  (stains  red  with 
eosin)  which  occurs  in  soft  fibromata.  The  tissue  may  be  rich  in 
blood  vessels  and  exhibit  a  tendency  to  hemorrhages.  Myxomata, 
pure  or  in  combination  with  other  connective  tissue  elements,  take 
origin  with  predilection  from  serous  tissues  (mesentery),  and  the 
cutis,  especially  around  the  umbilicus  (from  embryonic  remains 
of  the  umbilical  cord),  also,  but  more  rarely,  from  the  sheaths  of 
the  central  nervous  system  (brain  and  cord)  and  of  the  nerves. 
Myxomatous  tissue  forms  occasionally  the  stroma  or  part  of  the 
stroma  of  epithelial  organoid  tumors,  especially  in  certain  glandu- 
lar tumors  of  the  breast  and  salivary  glands  (myxoadenomata). 
Although  myxomata  consist  really  of  embryonic  tissue,  they  re- 
main generally  stationary,  growing  slow,  are  encapsulated  and 
display  often  fatty  cell  changes.  (Possible  origin  of  lipomata  from 
myxomata?)  Transitions  to  sarcoma  are  not  infrequent  and  the 
growth  is  always  suspicious. 

3.  Lipoma.  Lipoma  is  a  tumor  in  which  fat  tissue  is  the  essen- 
tial element.  It  is  a  very  slowly  growing,  usually  lobated,  expansive 
tumor.  Nevertheless,  lipomata  often  reach  great  size  and  weight 
and  become,  therefore,  troublesome.  Individually  the  construction 
of  lipomata  varies.  It  may  contain  much  connective  tissue  stroma, 
(lipoma  fibrosum),  or  occur  with  myxomatous  tissue,  or  with 
cartilage  or  with  bone,  especially  in  those  which  calcify  and  petrify. 
Generally  these  tumors  are  poor  in  blood  vessels  and  therefore 
present  regressive  changes,  but  occasionally  these  may  be  abun- 
dant (lipoma  telangiectaticum),  and  the  cells  appear  well  nourished. 
The  fat  contents  may  liquefy  and  thus  the  growth  becomes  cystic. 
They  are  frequent  in  the  skin,  from  which  they  project  as  pendulous 
growths  attached  by  a  pedicle.  They  also  take  origin  from  the  fat 
of  the  mesentery  and  elsewhere  (fatty  glands,  kidney,  rare  in  breast 
and  other  organs). 

Microscopically,  lipomata  are  pure  fat  tissue  with  many  varia- 
tions in  size  of  fat  cells.  In  the  early  stages  these  are  represented 


CHANGES  IN  LOCAL  CELL  RELATIONS          255 

by  fibroplasts  which  soon  accumulate  fat  within  their  protoplasm. 
This  remains  in  the  form  of  large  globular  drops  and  is  mostly 
neutral  fat  with  lipoid  admixtures.  Occasionally  the  embryonic 
cellular  character  is  maintained  and  thus  the  growth  is  sarcoma- 
tous.  Noticeable  is  a  multiple,  symmetrical  form  of  lipomata,  more 
or  less  in  the  course  of  nerves,  but  not  directly  connected  with  them. 
It  has  been  brought  into  connection  with  disturbances  of  internal 
secretion,  especially  in  the  hypophysis  cerebri  (pituitary  gland),  but 
this  is  uncertain.  There  seems  to  exist  a  hereditary  disposition  to 
these  tumors. 

Xantboma.  Under  this  term  are  included  yellowish  to  brownish 
patches  and  elevations  on  the  skin  of  hands,  arms,  forehead  and 
sometimes  other  situations.  They  are  often  symmetrical.  Their  seat 
is  the  corium  or  deeper  tissues.  In  younger  persons  they  are  apt  to 
be  nodular,  in  older  persons  they  are  generally  flat  and  become  con- 
spicuous after  forty  years  of  age  (liver  spots).  Microscopically  they 
show  increase  of  fibrous  tissue  in  the  cutis  which  is  infiltrated 
with  cords  of  fatty  and  pigment  cells.  They  are  closely  connected 
with  the  course  of  lymph  channels.  Pigmented  giant  cells  are  also 
found.  Rarely  their  growth  gains  momentum  and  a  sarcoma  de- 
velops. Chemically  the  fat  is  mostly  cholesterin.  Xanthomata  arise 
on  the  basis  of  hereditary  disposition. 

4.  Cbondroma.  Echondroma,  or  enchondroma,  is  a  cartilagi- 
nous tumor.  The  chondromata  grow  as  tuberous,  nodular  or  lobated 
growths  of  firm,  occasionally  somewhat  elastic  consistency  and 
are  often  of  characteristic  opalescent  luster.  Their  usual  origin  is 
in  the  perichondral  or  periosteal  tissue,  but  they  may  also  arise  in 
soft  parts  or  internal  organs.  The  growth  is  expansive;  sometimes, 
however,  it  pushes  its  way  along  veins  and  lymphatics  leading  to 
necrosis  of  their  walls.  Nutritive  disturbances  may  bring  about 
partial  softening  and  fusion  and  lead  to  canalization  and  cavity 
formation.  These  openings  may  later  be  filled  by  a  myxomatous 
tissue,  chondroma  myxomatosum.  Calcification  and  ossification 
are  frequent.  In  genuine  ossification  dissolution  of  the  cartilage  by 
a  young  vascular  cellular  tissue  occurs  which  is  differentiated  into 
bone.  Thus,  the  chondroma  may  become  wholly  or  partly  an 
osteoma.  Chondromata  are  also  mixed  with  fibrous  connective 


256  GENERAL  PATHOLOGY 

tissue  in  various  forms  of  differentiation  and  maturity.  There  exist 
complicated  tumors  of  the  salivary  glands,  especially  of  the  paro- 
tid, and  of  the  testicle,  in  which  cartilage  is  conspicuous.  These  are 
of  embryonic  and  developmental  derivation  and  will  be  considered 
in  the  teratoid  growths. 

While  chondromata  are  generally  slowly  growing,  clinically 
benign  tumors,  their  occasional  invasion  into  veins  and  lymphatics 
may  lead  to  extensive  intravascular  extensions  and  even  to  meta- 
stases  in  glands  and  in  the  lung.  This  seems  to  occur  especially  in 
osteoid  chondroma. 

Microscopically  the  chondromata  show  various  types  of  carti- 
lage formation  surrounded  by  a  vascular  connective  tissue  re- 
sembling the  perichondrium.  The  cartilage  does  not  present  the 
general  uniform  regular  maturity  and  differentiation  of  physiolog- 
ical cartilage.  The  ground  substance  remains  fibrillar,  occasionally 
shows  elastic  fibers  and  the  cell  capsule  is  also  less  completely 
formed  than  in  normal  cartilage.  Cells  vary  in  size  and  shape, 
in  number  in  a  capsule,  and  in  regularity  of  arrangement.  The 
tendency  to  cartilaginous  growths  seems  to  occur  largely  on  a 
hereditary  basis.  They  are  often  multiple,  in  the  form  of  small, 
pointed  projections  from  bones  (exostoses).  Some  seem  to  arise 
from  dislocated  embryonic  remains  in  situations  of  complicated 
development,  as  in  chondromata  and  mixed  growths  of  the  parotid 
region  (branchiogenic  tissue  of  branchial  clefts) . 

Special  mention  must  be  made  of  the  so-called  chordoma,  or 
ecchondrosis  clivus  Blumenbachii.  This  is  a  small  gelatinous  sub- 
dural  growth  of  the  spheno-occipital  fissure,  which  may,  however, 
break  through  the  dura  and  infiltrate  the  brain  and  also  break 
through  the  pharynx.  It  is  made  up  of  large  vesicular  cartilage 
cells  (physalides),  chondroma  physaliforme.  According  to  Rib- 
bert's  view,  which  is  now  generally  accepted,  it  is  a  derivative 
of  the  embryonic  chorda.  A  similar  tumor  has  been  described  in 
the  sacrum. 

5.  Osteoma.  This  is  a  tumor  in  which  bone  and  bone  cells  are 
the  essential  elements  from  inception  of  growth.  Like  physiological 
bone,  it  occurs  in  two  forms,  osteoma  durum,  eburneum,  the  com- 
pact form,  and  osteoma  spongiosum,  medullare,  the  porous, 


CHANGES  IN  LOCAL  CELL  RELATIONS          257 

spongy  form.  They  are  generally  situated  in,  or  peripheral  to,  bone, 
but  rarely  occur  in  soft  parts,  even  parenchymatous  organs.  Cen- 
tral osteomata  are  products  of  the  bone  marrow  or  take  origin  from 
cartilaginous  islands  in  the  marrow.  These  by  gradual  expansion 
resorb  the  cortex  of  the  physiological  bone  and  this  remains  simply 
as  a  shell.  Peripheral  osteomata  arise  from  the  periosteum. 

Pure  osteomata  are  slowly  growing,  expansive,  clinically  benign 
tumors.  Their  growth  seems  at  times  to  be  accelerated  by  trauma. 
Microscopically  their  tissue  consists  of  a  rather  irregular  arrange- 
ment of  bone  cells  and  matrix,  making  the  architecture  and  differ- 
entiation less  uniform  than  in  normal  bone.  Some  of  the  small 
osteomata,  the  so-called  hyperostoses,  are  probably  of  inflamma- 
tory origin.  Teeth  give  rise  to  dental  osteomata  or  dental  exostoses. 
Some  of  these  contain  enamel  and  are,  for  this  reason,  true  odonto- 
mata.  They  do  not,  however,  show  any  papillary  projections  into 
the  epithelium. 

(b)  Lymphoid  Tissue  Derivatives.  Lympboma.  This  is  a  tumor 
made  up  of  lymphoid  tissue  in  more  or  less  mature  development, 
which  does  not  display  destructive,  infiltrative  and  metastasizing 
qualities.  The  seat  of  lymphoma  is  the  lymphoid  tissue,  most  fre- 
quently in  glands  and  mucous  membranes;  occasionally  they  are 
found  in  kidneys,  liver,  lung  and  thyroid.  They  always  take  origin 
from  preexisting  lymphoid  tissue. 

True  lymphomata  must  be  differentiated  from  a  number  of 
productive  inflammatory  lesions  which  lead  to  somewhat  similar 
pictures  in  lymphoid  tissues.  These  are  especially  the  so-called 
Hodgkin's  disease  and  certain  forms  of  tuberculosis.  Hodgkin's  dis- 
ease consists  in  a  discrete  first  localized,  then  generalized,  enlarge- 
ment of  lymph  glands  and  spleen  without  any  characteristic 
blood  changes.  Microscopically  it  displays  the  characteristics  of  a 
productive  granulomatous  inflammation;  polymorphous  cells,  leu- 
cocytes, all  kinds  of  lymphocytes,  plasma  cells,  spindle  cells,  giant 
cells  and  many  eosinophiles.  Later  exist  tendencies  to  regression 
and  necrosis  and  fibrosis. 

Tuberculosis  is,  in  its  typical  manifestation,  easily  separated 
from  lymphoma.  There  are  certain  types  in  which  differentiation 
may  be  more  difficult  when  softening,  giant  cells  and  fibrosis  are 

17 


258  GENERAL  PATHOLOGY 

absent,  but  even  then  the  presence  of  fibroplasts,  tendency  to 
regression,  and  greater  irregularity  in  cell  proliferation  are  notice- 
able (see  more  especially  under  Hodgkin's  Disease  and  Tubercu- 
losis above,  also  under  Infective  Granulomata). 

The  lymphoma  consists  of  a  uniform  growth  of  mature  large  or 
small  lymphoid  cells  lying  in  a  delicate  reticulum,  but  showing 
no  structural  arrangement  into  follicles  with  germinal  centers, 
lymph-cell  cylinders  and  sinuses  such  as  a  normal  lymph  gland  does. 
It  is,  primarily  at  least,  strictly  localized,  remains  discrete  and  within 
the  glands  and  does  not  lead  to  adhesion  between  them  and  the  skin 
such  as  the  lymphosarcoma  does.  The  lymphomata  are,  however, 
frequently  multiple,  affecting  more  or  less  the  entire  lymphoid  ap- 
paratus, and  these  bear  a  close  relation  to  lymphatic  leucemia.  In 
fact,  lymphatic  leucemia  may  be  regarded  as  multiple  lymphomata 
plus  entrance  of  lymphoid  cells  into  the  circulating  blood.  But 
there  is  the  difference  that  leucemia  exhibits  generally  an  addi- 
tional more  diffuse  lymphoid  infiltration  into,  and  new  lymph  cell 
formation  in,  other  organs  of  the  hematopoietic  system  (bone 
marrow,  spleen),  and,  on  account  of  entrance  of  lymphoid  cells 
into  the  general  circulation,  lymphoid  cell  infiltrations  into  par- 
enchymatous  organs  (liver,  kidney).  These  are  absent  in  pure 
lymphomata. 

Cohnheim  has  described  a  pseudo  leucemia  which  is  represented 
by  all  anatomical  changes  of  lymphatic  leucemia  without  the 
increase  of  lymphoid  cells  in  the  circulation. 

(c)  Myeloid  Tissue  Derivatives.  Myeloma.  Myeloma  is  a  tu- 
mor whose  parenchyma  consists  of  myelocytes  or  myeloplasts  and 
occasionally  also  of  erythroplasts,  growing  from,  and  imitating, 
myeloid  tissue  of  the  bone  marrow.  The  myeloma  is  generally  of 
multiple  occurrence  and  appears  in  soft  nodes  or  infiltrations  which 
lead  to  atrophy  and  softening  of  the  affected  bone  and  frequently 
to  spontaneous  fracture. 

A  rare  type  of  the  myeloma  is  the  plasmacytoma,  in  which  the 
growth  consists  almost  entirely  of  large  plasma  cells. 

Contrasted  to  the  myeloma  is  the  diffuse  myeloid  leucemic 
or  pseudo-Ieucemic  hyperplasia  of  marrow  cells  which,  however, 
leaves  the  bone  intact.  In  the  leucemic  variety,  the  cells  circulate 


CHANGES  IN  LOCAL  CELL  RELATIONS          259 

in  the  blood  and,  therefore,  as  in  lymphatic  leucemia,  infiltrate 
parenchymatous  organs.  This  is  absent  in  the  pseudo-Ieucemic 
type.  In  myelomata  other  organs  remain  uninvolved  although 
rare  cases  with  metastasis  have  been  reported.  The  urine  con- 
tains albumose,  the  so-called  "Bence  Jones"  body. 

(d)  Pigmented  Tumors.  Melanoma,  or  Chromatopboroma  (pig- 
mented  moles) .  The  pigmented,  local,  stationary  growths,  exempli- 
fied by  the  pigmented  nevus  or  mole,  are  congenital,  developmental 
and  appear  as  soft,  uneven,  often  nodular  and  hairy  prominences 
on  the  skin.  The  lesion  is  to  be  traced  to  a  local  abnormal  mixture 
and  tumor-like  hyperplasia  of  tissue  (skin)  elements  (hamartoma). 
Not  infrequently  it  is  multiple,  follows  sometimes  in  the  course  of 
nerves  and  combines  with  multiple  fibromata  or  elephantiasic 
skin  hypertrophies.  It  is  not  exclusive  to  skin,  but  may  be  found 
in  the  form  of  pigmented  spots  in  the  brain,  and  spinal  cord. 

The  microscopic  appearance  of  the  skin  shows  a  fibrous  cellular 
increase  in  the  cutis  with  hypertrophy  of  papillae  and  an  abnorm- 
ally extensive  pigmentation.  This  occupies  the  lower  strata  of 
the  epidermis,  but  also  the  cutis  in  characteristic  spindle-shaped 
anastomosing  spheroid  flat  cells  (chromatophores).  In  the  deeper 
layers  of  the  cutis  these  cells  lie  more  or  less  diffuse  and  generally 
follow  the  blood  vessels.  In  the  upper  layer  and  in  the  papillae  they 
are  generally  arranged  in  well-circumscribed  nests  (nevus  cells). 
These  nests  contain  pigment,  intra-  and  extracellular,  but  not  all 
cells  show  pigment.  Characteristic  pigmented  spindle  cells  in  the 
cutis  are  seen  to  form  a  fine  delicate  network  of  anastomosing 
pigmented  processes  and  these  extend  to  the  epidermis  and  sur- 
round nests  of  other  nevus  cells. 

This  tumor-like  lesion  represents  a  localized  disturbance  in  the 
normal  pigment  metabolism  of  the  skin  and  this  is,  in  turn,  due  to 
the  faulty  arrangement,  development  and  pathological  hyper- 
plasia of  cells  charged  with  this  function.  Consequently  the  part 
of  the  skin  thus  affected  is  disorganized  (shown  by  absence  of  sweat 
and  sebaceous  glands,  and  hair  follicles).  The  abnormal  pigmenta- 
tion is  a  functional  expression  of  this  disorganization.  Just  how  this 
is  produced  is  uncertain.  It  is  assumed  that  it  is  the  product  of  the 
action  of  nuclear  substance  on  proteids  (oxydase  reaction)  or  that 


260  GENERAL  PATHOLOGY 

the  pigment  represents  an  intermediary  product.  The  derivation  of 
the  nevus  cells  is  also  still  disputed.  Some  think  them  epithelial, 
others  endothelial. 

(e)  Muscle  Tissue  Derivatives:  Myomata.  i .  Leyomyoma  (Myoma 
levicellulare).  The  leyomyoma  consists  of  smooth  muscle  fibers. 
The  leyomyomata  are  capsulated,  white,  globular  or  nodular 
growths  which,  on  section,  present  an  interwoven  arrangement  of 
thick  glistening  bands  and  coils,  at  times  somewhat  resembling  the 
gyrations  of  the  brain.  Microscopically,  the  muscle  fibers  are  seen 
in  wavy,  intimately  interwoven  ribbons  which  usually  follow  blood 
vessels.  Besides  muscle,  these  tumors  contain  a  variable  amount 
of  connective  tissue  stroma.  This,  in  older  myomata,  becomes  more 
prominent  and  conspicuous  (fibromyoma  or  "the  fibroid'*  of  the 
gynecologists).  Some  are  rich  in  cavernous  blood  vessels,  often, 
however,  they  are  poorly  vascularized.  For  this  reason  regressive 
metamorphoses  are  frequent:  edematous,  mucoid,  hyaline  degen- 
erations, even  necrosis  with  subsequent  calcification.  Osseous 
transformation,  even  with  bone  marrow  formation  may,  though 
rarely,  follow.  Not  infrequent  are  infections  of  myomata,  espe- 
cially in  the  uterus.  The  growth  may  then  undergo  putrid  softening. 
In  vascular  myomata  hemorrhages  are  frequent.  This  is  the  case 
more  especially  in  the  internal  soft  myomata  of  the  stomach. 

Myomata  are  generally  benign,  slowly  growing  tumors  but  may 
reach  tremendous  size  and,  therefore,  become  troublesome.  Rarely 
they  display  malignant  infiltrating  character,  although  histologi- 
cally  mature.  They  break  then  into  veins,  extend  intravascularly 
and  may  produce  metastases. 

The  leyomyoma  may  be  confused  with  spindle-celled  sarcomata 
or  cellular  fibromata  but  generally  allows  diagnosis  by  its  long 
slender,  rod-shaped,  round-ended  nuclei  which  lie  in  the  cell 
protoplasm  and  follow  its  fibrillar  curves.  The  fibroplast  has  a 
larger,  generally  less  chromatic  and  distinctly  spindle-shaped, 
pointed  and  straight  nucleus.  Connective-tissue  fibers  are  also  apt 
to  show  longitudinal,  wavy  striations  and  to  terminate  into  fine 
fibrils.  In  mixed  mature  growths  differential  stain  by  Van  Gieson's 
method  stains  connective  tissue  red,  muscle  tissue  yellow.  This 
method  fails,  however,  with  immature  connective  tissue. 


CHANGES  IN  LOCAL  CELL  RELATIONS          261 

The  leyomyomata  are  frequent  tumors  of  the  uterus,  in  which 
they  occur  in  submucous,  interstitial  or  subserous  form.  Sometimes 
they  are  displaced  into  the  broad  ligaments.  Subserous  and  sub- 
mucous  forms  often  assume  polypoid,  pediculated  shape.  In  the 
stomach  and  esophagus  they  are  found  occasionally  either  on  the 
outside  or  projecting  from  the  mucous  membrane  into  the  lumen 
(internal)  and  may  grow  to  tremendous  size.  They  also  spring 
from  other  muscle  tissue  in  bladder,  testicle,  prostate,  ovary,  etc. 

In  the  uterus  myomata  contain  often  a  greater  or  less  content  of 
glandular  elements.  These  are  held  to  arise  from  incorporated  parts 
of  the  Wolffian  body  or  dislocated  mucous  glands  during  embryonic 
development.  They  apparently  remain  stationary  and  take  no 
part  in  the  growths,  so  that  the  name  adenomyomata  which  is 
given  to  these  tumors  is  not  strictly  correct,  as  the  glandular  part  is 
not  a  real  tumor  element.  But  the  gland  acini  may  dilate  and  form 
cysts. 

Myomata  give  rise  to  myosarcomata  (see  later),  and  true  con- 
nective tissue  sarcomata  may  arise  from  the  connective  tissue  in 
the  myoma. 

2.  Rbabdomyoma  (Myoma  Striocellulare).  This  is  a  very  rare 
usually  congenital  or  developmental  growth  or  malformation 
(hamartoma).  Fully  mature  and  differentiated  it  is  even  rarer  than 
in  immature  and  sarcomatous  form.  It  has  been  described  in  the 
infantile  heart,  occasionally  in  striped  and  non-striped  muscle. 
I  saw  some  years  ago  a  sarcomatous,  immature  recurrent  form  in 
the  tongue  of  a  young  woman. 

(/)  Nervous  Tissue  Derivatives,  i.  Glioma  is  a  tumor  of  the 
brain,  spinal  cord  and  retina  which  is  derived  from  neuroglia.  The 
gliomata  are  made  up  of  a  variable  quantity  of  glia  cells,  fibrillar 
stroma  and  blood  vessels  and  display  a  tendency  to  hemorrhages 
into  the  tumor  (apoplexy).  Again,  others  are  apt  to  soften  and 
form  cavities  (cystic  glioma).  They  are  mostly  solitary,  rarely 
multiple,  and  take  origin  from  white  or  gray  matter.  Sometimes 
they  are  subendymal  and  grow  then  into  the  ventricles. 

Grossly,  they  are  grayish,  gelatinous,  pinkish  or  reddish  tumors, 
depending  upon  their  vascularity,  sometimes  well  circumscribed, 
but  often  diffusely  connected  with  the  surrounding  normal  nerv- 


262  GENERAL  PATHOLOGY 

ous  substance  so  that  they  are  not  sharply  outlined.  This  makes 
their  recognition  sometimes  difficult,  especially  when  hemor- 
rhages obscure  the  main  central  tumor  mass. 

Microscopically,  they  are  made  up  of  glia  cells  and  fibrils.  The 
glia  cells  are  characteristic  astrocytes,  spider  cells,  with  delicate 
fibrillar  processes  which  go  to  make  a  looser  or  denser  felt  like  net- 
work within  which  rest  glia  nuclei.  When  the  fibrillar  network  is 
dense,  gliomata  are  hard,  when  more  cellular,  they  are  soft.  With 
increasing  cell  contents  cell  differentiation  and  maturity  become 
more  irregular,  less  complete  and  polymorphous  and  glial  giant  cells 
appear.  Thus  all  gradations  to  the  gliosarcomata  may  be  found. 

In  some  gliomata  epithelial  structures  and  tubules  appear.  They 
are  derived  from  embryonic  remains  of  the  neural  tube.  Frequently 
they  are  arranged  in  the  form  of  rosettes  (neuroepithelioma  glioma- 
tosum).  Sometimes  these  epithelial  growths  become  extensive  and 
have  been  described  as  giving  rise  to  cancer. 

A  type  of  glioma  of  the  spinal  cord  is  situated  around  the  spinal 
canal  and  for  some  distance  follows  its  longitudinal  axis.  It  softens 
readily  and  thus  leads  to  central  long  cavitation  in  the  cord 
(syringomyelia). 

2.  Neuroma.  The  true  neuroma  is  a  tumor  consisting  of  nerve 
fibers  and  ganglion  cells.  A  number  of  tumors  have  been  included 
which  are  intimately  connected  with  nerves  but  take  origin  from 
the  connective  tissue  of  the  end,  or  perineurium.  These  are,  there- 
fore, regarded  as  false  neuromata  or  neurofibromata.  The  neuro- 
fibromata  occur  generally  in  multiple,  subcutaneous,  small  and 
large  nodules,  diffusely  disseminated  over  the  whole  skin,  freely 
movable  and  not  tender.  This  is  generally  referred  to  as  von 
Recklinghausen's  disease.  The  claim  has  recently  been  made,  how- 
ever, that  these  so-called  neurofibromata  are  of  nerve  origin  in 
which  the  newly  formed  tissue  is  not  differentiated  to  nerve  fib- 
ers, but  assumes  fibrous  appearance.  This  claim  needs  further 
substantiation. 

The  true  neuromata  occur  in  the  central  and  peripheral  nervous 
system  and  may  be  made  up  of  medullated  or  non-medullated  nerve 
fibers.  Besides  the  fibrils,  they  contain  a  greater  or  lesser  number 
of  nerve  cells  (neuroma  ganglionare). 


CHANGES  IN  LOCAL  CELL  RELATIONS          263 

The  cellular  neuromata,  which  are  composed  mainly  of  ganglion 
cells  in  various  stages  of  differentiation,  are  rare  tumors  of  the 
central  nervous  system,  the  sympathetic  system  and  the  chro- 
maffin  system  (medulla  of  suprarenal  gland  and  paraganglia).  Often 
they  are  quite  undifferentiated  and  sarcomatous  (resembling  lym- 
phoid  cells)  in  character  (see  under  Neuroma  Sarcomatodes).  Then 
again  they  are  better  differentiated  to  nerve  cells,  slightly  pigmented 
and  arranged  in  rosettes  with  hollow  center  and  variable  amount 
of  delicate  fibrils  which  take  origin  from  the  bodies  of  the  nerve 
cells.  Marchand  has  proposed  the  name  neurocytoma  for  these 
tumors.  Those  taking  origin  from  the  suprarenal  medulla  and  para- 
ganglia  are  often  distinctly  chromaffmic  in  character  (carotid 
gland).  They  are  apt  to  behave  like  malignant  sarcomata.  Some 
remain  local  and  stationary.  Clinically  important  are  the  so-called 
amputation  neuromata  which  occur  as  the  result  of  excessive 
nerve  regeneration  after  amputation,  usually  also  with  excessive 
cicatrix  formation.  They  lead  to  very  painful  nodules  in  the 
stump. 

B.  IMMATURE,  UNDIFFERENTIATED,  HISTOID,  DISSEMINATING 
TYPES.  Sarcomata.  The  name  sarcomata  is  derived  from 
(rapt-  —  flesh,  a  term  given  to  these  tumors  on  account  of  their 
gross  appearance.  To  this  group  belong,  in  a  wider  sense,  all  imma- 
ture, generalizing,  histoid  growths.  They  represent,  therefore, 
tumors  of  tissues  of  incomplete  development  and  differentiation. 
Even  as  far  as  their  development  and  differentiation  go,  they  pre- 
sent unusual  and  often  atypical  cell  forms.  The  predominating, 
distinguishing  component  of  sarcomata  is  represented,  therefore, 
by  immature  cells  while  the  formation  of  intercellular  substance 
or  stroma  is  absent  or  incomplete.  Such  tumors  are  eminently 
malignant.  They  are  destructive,  infiltrative,  recur  rapidly  after 
excision  and  produce  metastases. 

The  term  sarcoma  in  the  strict  sense  is  employed  by  some  only 
to  designate  those  immature  growths  which  take  their  origin  from 
connective  tissues,  but  the  close  histological  similarity  and  manner 
of  growth  which  the  other  immature  tumors  of  the  histoid  group — 
muscle,  glia,  nervous  substance — bear  to  those  of  the  connective 
tissue  group,  makes  it  convenient  and  permissible  to  include  all 


264  GENERAL  PATHOLOGY 

immature  histoid  tumors  in  this  term  and  differentiate  those  of 
immature  muscle,  glia  or  nervous  cells  by  a  descriptive  prefix  such 
as  glioplastic,  myoplastic  and  neuroplastic  sarcoma.  This  separates 
them  also  from  occasionally  occurring  connective  tissue  sarcomata 
which  take  their  origin  from  the  stroma  of  gliomata,  myomata  or 
neuromata. 

The  exact  origin  and  early  histogenesis  of  sarcomata  are  practi- 
cally unknown.  We  are  only  sure  of  one  point,  that  sarcomata  rep- 
resent embryonic  tissue  of  one  kind  or  another  which  has  lost  at 
one  point  of  its  development  the  power  of  further  differentiation  to 
maturity  and  simply  maintains  its  vegetative  functions.  It  is  pos- 
sible that  at  least  some  sarcomata  take  origin  from  embryonic 
tissue  or  cell  nests  which  have  never  fully  developed  but  have 
remained  isolated  within  mature  tissues  until  certain  environ- 
mental influences  have  stimulated  or  released  them  to  grow  (see 
later  under  Etiology  of  Tumors). 

The  sarcomata  are  primarily  solitary  tumors  but  at  times  multi- 
ple. They  grow  rapidly  and  acquire  considerable  size  in  the  form 
of  nodular,  irregular,  poorly  outlined,  diffuse,  not  circumscribed 
growths,  intimately  connected  with  adjoining  parts  and  not  en- 
capsulated. Rapidity  of  growth  in  sarcomata  varies  and  goes  more 
or  less  hand  in  hand  with  degree  of  differentiation.  The  lower,  the 
less  differentiated,  in  type,  the  greater  is  the  rapidity  of  growth, 
the  greater  lack  of  restraint,  and  the  more  foreign  is  the  relation  to 
the  host.  Intimately  connected  with  these  characters  are  regres- 
sive changes. 

The  greater  the  cell  contents,  immaturity  in  cells,  and  loss  of 
normal  cell  arrangement,  the  greater  the  tendency  to  degeneration, 
necrosis,  cavitation,  inflammation  and  ulceration.  Thus  ugly,  so- 
called  fungoid  tumors  are  produced  and  these  very  features  gave 
rise  to  the  name  sarcoma.  Vascularity  also  varies  considerably,  al- 
though, generally  speaking,  sarcomata  are  well  supplied  with  blood 
vessels  and  capillaries.  For  this  reason  many  bleed  easily  and 
become  hemorrhagic. 

As  rapidity  of  growth  is  greater  in  the  least  differentiated  types, 
so  also  the  degree  of  malignancy  goes  hand  in  hand  with  the  degree 
of  differentiation  and  approach  to  normal  tissue  arrangement. 


CHANGES  IN  LOCAL  CELL  RELATIONS          265 

The  entirely  undifFerentiated  forms  with  no  attempt  of  arrange- 
ment grow  wildest  and  produce  most  extensive  metastases. 

Sarcoma  cells  break  easily  into  their  own  blood  vessels,  are  car- 
ried along  to  a  suitable  tissue  soil  for  growth  and  thus  metastasize 
by  preference  through  the  blood  stream.  But  this  occurs  not  to  the 
exclusion  of  occasional  generalization  by  the  lymph  stream.  This 
is  not  infrequent  in  sarcomata  taking  origin  from  lymphoid  tissues 
(glands). 

The  general  effects  of  sarcomata  on  a  host  are  pronounced 
and  consist  of  anemia,  emaciation  and  local  effects  but  without  the 
cachexia  characteristic  of  cancers. 

Sarcomata  are  best  classified  according  to  the  degree  of  differ- 
entiation and  tissue  development  which  they  attain.  Consequently 
we  may  distinguish: 

i.  Entirely  Undifferentiated  Forms.  These  tumors  consist  en- 
tirely of  cells  which  in  form  and  in  arrangement  bear  no  resem- 
blance to  any  mother  tissue.  The  cells  are,  therefore,  of  the 
earliest,  quite  undifferentiated,  embryonic  period,  and  can  be 
compared  only  to  the  youngest  cells  from  granulation  tissue. 
But  whereas  the  latter  mature  and  soon  allow  a  definition  of 
their  character,  these  sarcomata  continue  throughout  their 
existence  in  this,  the  lowest  form  of  cell  development.  These 
tumors  are  composed  of  small  or  large  cells,  only  with  occasional 
spindle,  giant  or  elliptical  cells.  Intercellular  substance  is  absent 
or  very  rudimentary. 

Of  these  sarcomata  it  is  customary  to  distinguish  two  types: 

(a)  The  small-  (round)  cell  sarcoma,  soft  marrow-like,  white  or 
reddish  tumors,  often  referred  to  as  encephaloid  on  account  of 
their  soft  brain-like  consistency.  They  may  form  nodules,  but 
frequently  infiltrate  diffusely.  They  are  vascular,  grow  very  rapidly 
and  metastasize  extensively  and  early.  Microscopically,  they  show 
diffuse  aggregates  of  small  round,  sometimes  slightly  irregularly 
shaped  cells  with  round,  relatively  large  nuclei.  The  cells  disin- 
tegrate so  rapidly  (autolysis)  that  frequently  the  body  is  no  longer 
visible  or  only  to  be  seen  in  the  form  of  a  faint  halo  around  the 
nucleus.  The  cells  are  often  dense  around  the  blood  vessels.  They 
occur  especially  from  intramuscular,  periosteal,  subserous  con- 


266  GENERAL  PATHOLOGY 

nective  tissue,  then  also  from  the  skin  and  less  frequently  from 
other  viscera. 

(6)  The  large-  (round)  celled  sarcoma  differs  from  the  foregoing 
only  in  larger  size  of  cells  and  occasionally  slightly  advanced 
differentiation.  Cells  may  then  appear  elliptical,  elongated  and 
possess  a  fine  reticular  stroma  which  separates  groups  of  cells  (so 
called  alveolar  sarcoma).  Cells  and  reticulum  are  intimately 
associated,  unlike  organoid  tumors  (see  later)  in  which  such  inti- 
macy between  tumor  cells  and  the  more  abundant  stroma  never 
exists.  In  origin  and  behavior  it  is  exactly  like  the  small-celled 
sarcoma. 

2.  Somewhat  Differentiated  Forms,  (a)  The  spindle-celled  sar- 
comata are  a  somewhat  more  solid,  reddish  white,  often  better  local- 
ized and  not  so  rapidly  growing  and  generalizing  group  of  tumors. 
They  may  remain  local.  Microscopically,  they  are  made  up  of  small 
or  large  fibroplastic  spindle  cells.  The  large  spindle-celled  type 
appears  to  be  more  malignant.  These  tumors  shade  gradually 
through  different  forms  to  the  fibrosarcomata. 

(6)  The  giant-cell  sarcoma  includes  periosteal,  occasionally  medul- 
lary growths  of  bone  (in  jaw,  vertebrae,  long  bones).  They  form 
the  largest  number  of  the  so-called  Epulis  (from  «ri,  on,  and 
ov\ovt  gum,  that  is,  sitting  on  the  gum).  It  is  really  a  mixed-cell 
sarcoma  in  which  a  variety  of  more  or  less  advanced  connective 
tissue  cells  occur,  mostly  fibroplasts,  with  a  conspicuous  number 
of  giant  cells  which  resemble  the  myeloplaxes  or  megakariocytes 
of  the  bone  marrow.  A  tendency  to  bone  formation  is  occasionally 
seen  (transition  to  osteosarcoma).  They  are  slowly  growing,  not 
generalizing,  local  growths  and  have  for  this  reason  and  on  account 
of  the  variety  of  cell  which  they  contain  been  regarded  by  some  as 
inflammatory  in  character. 

(c)  Melanosarcoma  is  a  deeply  dark-pigmented  and  very 
malignant  tumor  made  up  of  pigment  cells  or  melanoplasts.  The 
pigment,  like  that  in  the  nevus,  is  Fe  free.  The  cells  are  in  all 
probability  derived  from  pigment  cells,  either  of  normal  situation 
(eye,  choroid,  suprarenal,  skin)  or  from  nevus  cells  which  become 
active.  They  show  either  a  diffuse  sarcomatous  manner  of  growth 
or  an  alveolar,  almost  cancerous  arrangement  with  a  varying 


CHANGES  IN  LOCAL  CELL  RELATIONS          267 

amount  of  supporting  stroma.  The  shape  and  size  of  cells  and 
pigmentation  vary  greatly  in  individual  tumors.  Some  of  the  better 
differentiated  types  show  delicate  cells,  finely  pigmented,  occa- 
sionally with  dendrites  or  fibrillar  processes  such  as  are  found  in  the 
chromatophores  of  the  skin.  Others  are  rich  in  large,  plump,  some- 
times spindle-shaped  cells  and  contain  an  abundance  of  coarse 
pigment.  But  every  tumor  shows  non-pigmented  cells  and  extra- 
cellular pigment.  Sometimes  the  microscopic  examination  dis- 
closes a  disappointingly  small  amount  of  pigment  in  tumors  which 
are  grossly  quite  dark.  Blood  and  urine  may  contain  the  same  pig- 
ment, melanin,  the  nature  of  which  is  still  quite  uncertain  (see 
under  Melanin  in  Pigmentary  Degenerations). 

Opinions  differ  as  to  the  nature  of  these  cells  and  character  of 
the  tumor.  Those  regarding  chromatophores  as  epithelial  regard 
the  cells  and  the  tumor  essentially  as  an  epithelial  growth  (can- 
cer), those  regarding  them  as  connective  tissue  consider  them 
sarcomatous.  As  already  stated,  the  manner  of  growth  is  at  times 
quite  diffuse  and  histoid  as  in  sarcomata,  in  others  alveolar  in 
which  fibrous  stroma  separates  nests  of  cells.  This  latter  is,  how- 
ever, not  the  common  appearance  and  the  alveolar  arrangement  is 
never  so  completely  developed  as  in  the  true  cancer  so  that  reten- 
tion of  the  growth  under  sarcomata  seems  justified.  Their  rapid, 
vascular,  extensive  generalization  is  also  more  like  that  of  sar- 
comata. It  is  possible,  however,  that  some  of  the  melanomata  are 
pigment  cancers  which  would  make  the  melanomata  of  dualistic 
derivation.  The  liver  is  especially  liable  to  large,  nodular,  soft  and 
deeply  pigmented  metastases;  also  the  serous  surfaces  (pleura, 
peritoneum,  etc.). 

3.  Histoid,  or  More  Fully  Developed,  Sarcomata.  These  display 
greater  tendency  to  the  formation  of  tissues  by  greater  maturity 
and  a  more  definite  arrangement  of  cells.  Although  these  are 
numerous  and  dominate  the  tumor  picture,  they  give  rise  to  an  ap- 
preciable intercellular  substance.  These  growths  approach,  there- 
fore, the  mature  tumors,  and  this  relation  is  further  emphasized  by 
transitional  growths  which  stand  on  the  borderline  between  the 
two. 


268  GENERAL  PATHOLOGY 

The  sarcoma  character  is  preserved  by  greater  cell  predomi- 
nance, greater  cell  activity  and  a  somewhat  more  atypical  arrange- 
ment of  the  parts. 

(a)  Fibroma  Sarcomatodes  (Fibrosarcoma) .     Stands  close  to  the 
cellular  fibroma.  It  is  occasionally  still  encapsulated,  but  richer  in 
cells  and  poorer  in  fibers  than  the  fibromata.  It  is  generally  local, 
but  has  tendency  to  recurrence. 

(b)  Myxoma      Sarcomatodes      (Myxosarcoma) .     Distinguished 
from  myxoma  by  richness  in  cells  and  irregularity  in  develop- 
ment,   arrangement   and    production  of  mucus.   It  grows  more 
rapidly  and  is  apt  to  metastasize.  Its  preferred  places  of  origin 
are  those  of  the  myxoma. 

(c)  Lipoma  Sarcomatodes  (Liposarcoma) .     A  rare  tumor  show- 
ing young  (sarcomatous)  fat  cells  with  a  variable  amount  of  fat. 
Relatively  benign  and  often  encapsulated. 

(d)  Cbondroma  Sarcomatodes  (Cbondrosarcoma) .     Opaque,  hya- 
line tumors  of  white  luster,  firm  and  of  destructive  tendency.  Often 
combined  with  myxoid,  fibrous  and  vascular  tissue.  The  cells  are 
poorly  differentiated  cartilage  cells;  the  intercellular  substance 
is  incomplete  and  fibrillar  (these  tumors  must  be  differentiated 
from    the    sarcomatous    teratomata,    see    later).    Origin    as    in 
chondroma. 

(e)  OsteomaSarcomatodes(Osteosarcomd).     These  arise  with  pref- 
erence  from   periosteum  of  long  bones,    lead  to  spindle-shaped 
thickenings  of  the  bone  and  are  to  be  differentiated  from  other 
periosteal  sarcomata.  They  consist  of  sarcomatous,  cellular  tissue, 
myxoid  tissue,  cartilage  and  osseous  lamella?  and  calcified  spicules. 
In  the  genuine  form  bone  is  produced  in  larger  amounts.  In  these 
periosteal  osteosarcomata  a  radiating  structure  of  parallel  bony 
spicules  and  bars,  arranged  perpendicularly  to  the  bone  shaft,  is 
produced. 

Microscopically,  these  tumors  show  a  varied  picture:  undiffer- 
entiated  sarcoma  cells,  spindle  cells,  cartilaginous  cells,  calcified 
rudimentary  bone  and  better  developed  bone.  Occasionally  bone 
marrow  cells  are  seen  in  bony  parts.  All  cell  types  represent  differ- 
ent stages  of  differentiation  of  one  original  tumor  focus. 


CHANGES  IN  LOCAL  CELL  RELATIONS          269 

Central,  so-called  medullary  sarcomata  of  bone  show  much  less 
tendency  to  bone  formation.  They  are  very  cellular,  vascular,  and 
more  destructive  and  malignant  than  the  periosteal  type.  They 
break  through  the  bony  cortex  early,  soften  and  thus  become 
hemorrhagic  and  cystic.  In  type  they  are  either  spindle  or  round 
celled,  sometimes  multinuclear,  giant  celled,  and  grow  in  alveolar 
or  perivascular  fashion.  They  occur  usually  in  juvenile  growing 
bone  at  the  junction  of  shaft  and  epiphysis,  generalize  rapidly 
(lung)  and  recur  rapidly. 

(/)  Lymphosarcoma.  This  takes  origin  from  lymphoid  tissue  of 
glands,  mucous  membranes,  spleen,  tonsils,  etc.  It  occurs  solitary 
or  multiple.  As  in  the  case  of  benign,  mature  lymphomata  (v.s.) 
it  must  be  carefully  differentiated  from  the  inflammatory  lymphoid 
tissue  hyperplasias  with  which  it  has  some  gross  and  microscopic 
resemblances.  These  points  are  fully  discussed  in  connection  with 
infective  granulomata  and  lymphoma.  Very  close  is  the  histological 
resemblance  to  small  or  large  round-celled  sarcomata  of  connec- 
tive tissue  derivation.  The  lymphosarcoma  shows  small  round  cells 
embedded,  as  in  lymphoid  tissue,  in  a  fine  intimately  connected 
reticulum.  The  cells  of  the  lymphosarcoma  are  lymphoplasts  closely 
resembling  the  cells  in  the  germinal  center  of  lymph  glands. 
Moreover,  the  lymphosarcoma  grows  and  metastasizes,  frequently 
by  the  lymph  stream  and  into  other  lymphoid  tissue,  differently 
from  the  connective  tissue  sarcoma. 

One  form  is  solitary,  grows  rapidly,  infiltrates  and  metastasizes 
by  lymph  circulation.  It  usually  takes  origin  from  mediastinal 
glands.  It  grows  into,  and  expands  in  fan-like  fashion  in,  the  ad- 
joining organs:  lungs,  pleurae,  pericardium. 

The  second  form  commences  as  a  multiple  growth  and  displays 
equally  as  aggressive  tendencies  as  the  first.  In  this  type  lym- 
phosarcomatous  cells  may  break  into  the  blood  streams  and  lead 
to  considerable  increase  of  lymphoid  cells  in  the  circulation.  Such 
cases  as  combine  the  picture  of  a  multiple  malignant  tumor  with  a 
blood  picture  of  lymphatic-Ieucemia  are  spoken  of  as  sarcoleu- 
cemia.  The  cells  here  are  usually  large  and  undeveloped.  To  this 
group  of  tumors  belongs  the  chloroma,  really  a  lymphosarcoma 
carrying  a  greenish  pigment, 


270  GENERAL  PATHOLOGY 

(g)  Myeloma  Sarcomatodes.  Rapidly  growing  rare  tumors  of  im- 
mature myelocytes  (large  mononuclear  cells  with  central  nucleus,  as 
yet  smooth  or  with  few  granules;  myeloplasts).  They  may  resemble 
fetal  bone  marrow  by  the  presence  of  small  erythroplastic  islands. 

(b)  Myoma  Sarcomatodes  (Myosarcoma) .  Sarcomatous  tumors 
of  immature  muscle  cells.  As  in  mature  types,  there  are  two  classes : 

(a)  Leyomyoma  Sarcomatodes.  The  more  frequent  of  the  two. 
In  uterus,  stomach,  bladder,  ovaries  and  kidneys;  most  frequent  in 
uterus.  Generally  takes  origin  from  a  benign,  mature  myoma  (in 
about  2^  per  cent,  of  cases)  which  for  certain  unknown  reasons 
begin  to  proliferate  more  rapidly  and  remain  low  in  cell  differentia- 
tion. Thus  deviation  from  appearances  of  typical  smooth  muscle 
fibers  becomes  greater  and  greater  and  the  arrangement  less  regu- 
lar, ultimately  lost.  These  genuine  myosarcomata  must,  of  course, 
be  differentiated  from  connective  tissue  sarcomata  which  occa- 
sionally arise  from  the  connective  tissue  stroma  of  myomata.  The 
leyomyoma  Sarcomatodes  infiltrates  and  metastasizes  like  other 
sarcomata. 

(/3)  Rbabdomyoma  Sarcomatodes.  A  very  rare  (v.s.)  tumor  of 
poorly  differentiated,  immature  striped  muscle  fibers.  The  striation 
is  often  rudimentary  and  distinction  from  fibrosarcomata  may  be 
difficult.  It  is  generally  rich  in  glycogen.  The  cells  are  round  or 
young  spindles  and  cylinders  and  the  striation  sometimes  only 
indicated  at  the  periphery  of  fibrils.  The  nuclei  may  be  central 
or  peripheral.  A  mucoid  stroma  is  sometimes  present.  The  sarcoid 
rhabdomyomata  are  frequently  congenital  (kidney,  heart)  but 
may  rarely  make  their  appearance  in  any  muscular  organ  later 
in  life  (tongue,  uterus,  bladder,  skeletal  muscle).  They  infiltrate 
diffusely  or  grow  on  the  surface. 

(i)  Glioma  Sarcomatodes  (Gliosarcoma).  A  tumor  composed  of 
rapidly  proliferating,  incompletely  matured  and  atypical  glia 
cells.  Neuroglia  fibrils  and  processes  are  only  rudimentary.  They 
are  usually  very  vascular  and  have  an  indefinite,  diffuse  relation 
to  the  surrounding  nervous  substance.  Transitional  tumors  be- 
tween the  sarcomatous  gliomata  and  cellular  gliomata  are  fre- 
quent. Although  histologically  of  sarcomatous,  immature  type  the 
gliosarcoma  does  not  metastasize  in  other  organs  and  very  excep- 


CHANGES  IN  LOCAL  CELL  RELATIONS          271 

tional  is  metastasis  into  even  the  nervous  system  (isolated  cases). 
The  favored  seat  is  the  brain  and  retina.  It  occurs  in  the  latter  as  a 
rapidly  growing,  hemorrhagic  tumor,  frequently  bilateral,  which 
destroys  the  eye  and  softens.  It  finally  protrudes  as  a  fleshy  reddish 
tumor  mass  from  the  necrotic  orbit.  This  is  not  infrequent  in 
infants  (congenital).  The  gliosarcomata  of  the  brain  also  possess 
marked  power  of  growth,occasionally  breaking  through  the  convex 
surface  of  the  brain  and  dura  and  attaching  itself  to  the  bony  skull 
which  it  brings  to  necrosis.  After  (surgical)  decompression  it  may 
force  open  the  bony  flap  and  grow  as  a  soft  fleshy  mass  through 
the  scalp. 

Gliosarcomata  enclose  at  times,  like  gliomata,  neuroepithelial 
acini  or  rosettes. 

(k)  Neuroma  Sarcomatodes  (Neurosarcoma) .  Malignant,  sarco- 
matous  tumors  of  the  nerve  cells  are  very  rare,  but  on  account  of 
their  undifferentiated  (small  round-celled)  character  they  may  be 
mistaken  at  times  for  ordinary  sarcomata.  The  sympathetic  and 
chromaffinic  systems  are  favored  seats  (medulla  of  adrenal)  for 
tumors  of  ganglion  cells  in  various  stages  of  differentiation.  They 
carry  all  the  malignant  destructive  and  metastasizing  qualities 
of  true  sarcomata.  Microscopically,  they  present  either  more 
typical  epithelial  glandular  parts  (like  the  embryonic  neural  canal) 
or  solid  nests  of  immature  ganglion  cells,  not  infrequently  arranged 
in  the  form  of  more  or  less  complete  rosettes  (c/.  Neuroma,  above) . 

II.    ORGANOID   TUMORS 

INTRODUCTION.  The  tumors  considered  so  far  were  of  simple  tis- 
sues (histoid).  They  represent  autonomous  growths  whose  paren- 
chyma is  made  up  of  either  connective,  muscular  or  nervous  tissues. 
Mixtures  may  occur,  but  the  components  retain  throughout  their 
own  tissue  individuality  and  make-up. 

In  organoid  tumors,  on  the  other  hand,  a  more  elaborate  con- 
struction of  the  tumor  is  noticeable  in  a  definite  more  or  less  cor- 
related growth  and  arrangement  of  tumor  parenchyma  and  a 
connective-tissue  frame.  They  approach,  therefore,  organ  construc- 
tion, more  especially  of  glandular  organs,  for  the  parenchyma  of 
these  tumors  is  made  up  of  cells  derived  from  epithelium.  Organoid 


272  GENERAL  PATHOLOGY 

tumors  are,  therefore,  also  spoken  of  as  fibroepithelial  growths.  The 
combination  of  parenchyma  and  stroma  may  be  fully  coordinated, 
mature,  or  irregular,  showing  emancipation  of  epithelium  from 
the  stroma  in  an  uncoordinated,  unrestrained,  immature  manner 
of  growth.  Under  these  conditions  epithelial  cells  break  away  from 
the  original  growth  and,  being  carried  by  the  lymph  and  occasion- 
ally blood  stream,  settle  and  metastasize  in  other  organs.  These 
tumors  are  known  as  cancers  or  carcinomata. 

A.  MATURE,  DIFFERENTIATED,  STATIONARY  TYPES,  (a)  Papil- 
lomata.  Papillomata  are  tumors  taking  origin  from  surface  epi- 
thelium. Their  connective  tissue  stroma  projects  as  a  vascular, 
branching  stem  from  the  surface  of  their  origin.  Stem  and  branches 
are  spoken  of  as  papillae  and  vary  much  in  size  and  shape.  They 
may  be  short,  thick  and  nodular,  or  long  and  cylindrical.  The 
terminal  branches  often  show  marked  attenuation  and  vascularity. 
Main  branches  and  stem  are  covered  throughout  by  some  form  of 
surface  epithelium:  squamous,  cylindrical,  or  ciliated. 

Papillomata  are  the  usual  warty  growths.  Depending  upon  the 
amount  of  connective  tissue  support,  they  are  either  hard  or  soft. 
The  hard  variety  develops  especially  from  the  skin  and  mucous 
membranes  (pharynx,  larynx,  cervix,  vagina,  urinary  bladder, 
ovary).  It  is  lined  by  squamous  epithelium  which  exhibits  great 
tendency  to  become  horny  (keratinize) .  The  growth  projects  in  the 
form  of  vascular  villous  excrescences.  These  are  apt  to  break  off  and 
so  give  rise  to  severe  repeated  hemorrhages,  or  they  are  discharged 
with  the  excretions  (urine).  Rarer  are  papillomata  of  the  choroid 
plexus  in  the  brain.  Papillomata  are  generally  benign,  but  may  be- 
come cancerous. 

To  the  group  of  surface  epithelial  tumors  belong  also  the  so- 
called  cholesteatomata  or  pearl  tumors,  growths  occurring  in  its  soft 
membranes  of  brain  and  cord  but  more  frequently  in  the  middle 
ear  and  pelvis  of  the  kidney  and  ureter.  These  are  small  globular, 
nodular  formations  of  white,  pearly  appearance  and  brittle  con- 
sistency. Microscopically,  these  masses  are  made  up  of  structureless 
scales  held  together  by  a  capsule  lined  by  undifferentiated,  flat 
cells.  They  arise  in  many  instances  on  an  inflammatory  basis. 
This  is  especially  the  case  in  the  middle  ear,  where  they  occur 


CHANGES  IN  LOCAL  CELL  RELATIONS          273 

on  the  basis  of  long-continued  granulomatous  inflammations.  They 
are  in  all  probability  derived  from  epidermis  although  some  have 
regarded  them  as  endothelial. 

(6)  Adenomata.  These  are  the  largest  and  most  important 
group  of  mature,  fibroepithelial  tumors.  They  take  origin  from 
glandular  tissue  and  preserve  in  their  growth,  more  or  less,  the 
glandular  structure,  that  is,  collections  of  epithelial  tubules  (alveoli, 
acini)  which  are  enclosed  by  a  basement  membrane  and  held 
together,  and  separated,  by  varying  amounts  of  mature  fibrous 
connective  tissue.  Tubules  or  acini  show  an  orderly  arrangement 
of  their  lining  epithelium  in  one  definite  epithelial  layer.  Cells 
display  generally  secretory  activity. 

The  approach  to  normal  glandular  organs  is,  therefore,  great  in 
adenomata,  but  their  independent,  autonomous  tumor  character 
is  shown  by  greater  production  of  glands,  and  a  somewhat  irregu- 
lar shape  and  order  of  arrangement.  Furthermore,  the  organoid 
development  is  limited  only  to  the  formation  of  glandular  tissue. 
It  does  not  form  connected,  structurally  related  lobes  or  even 
lobules  as  in  true  glands.  A  system  of  coordinated  ducts  does  not 
exist,  but  generally  only  incomplete,  aborted  duct  formation  with- 
out any  relation  to  functional  demands.  Consequently,  stagna- 
tion of  secretion  in  tubules  is  not  infrequent  in  adenomata  and 
thus  develop  cystadenomata. 

Not  all  adenomata  are  fully  or  highly  developed.  In  some  the 
glands  remain  primitive  and  the  lining  epithelium  is  poorly  de- 
veloped and  defined,  in  others  the  bulk  of  the  tumor  may  resemble 
only  gland  ducts.  The  relationship  of  glandular  parts  to  their  stroma 
also  shows  many  variations.  Some  are  predominatingly  glandular. 
Here  the  growth  of  glands  is  massive,  abundant  and  the  connective 
tissue  entirely  subordinated  to  it  (pure  adenomata).  Contrasting 
with  these  are  the  fibroadenomata  in  which  the  connective  tissue 
growth  may  be  sufficiently  great  to  make  them  resemble  fibromata 
with  aberrant  glands.  Some  adenomata  are  mixed,  parts  being 
purely  adenomatous,  others  more  fibrous.  If  the  fibrous  tissue  inti- 
mately surrounds  and  follows  the  gland  in  the  form  of  thick  connec- 
tive tissue  sheaths,  the  tumor  is  termed  fibroadenoma  pericanali- 
culare.  Occasionally,  however,  the  surrounding  fibrous  tissue  grows 

18 


274  GENERAL  PATHOLOGY 

strongly  towards  the  glandular  lumina,  in  parts  compresses  and 
even  projects  into  them.  This  tumor  is  spoken  of  as  fibroadenoma 
intracanaliculare.  The  stroma  undergoes  at  times  secondary 
changes,  becomes  mucoid,  hyaline,  etc. 

Adenomata  may  take  origin  from  all  internal  and  external 
glandular  organs.  They  present  themselves  as  globular,  nodular, 
mostly  encapsulated  tumors.  On  the  surface  they  may  be  smooth, 
often,  however,  lobular,  villous  or  polypoid,  but  always  well  cir- 
cumscribed. Frequent  seats  are  secretory  glands  which  by  environ- 
ment (productive  inflammation)  or  involution  (breast,  sex  organs) 
are  predisposed  to  unbalanced  cell  action.  Some  originate  from 
embryonic  glandular  rests  (WolfFian  body)  or  undeveloped  organ 
remains  (in  kidney,  testicle,  ovary,  etc.). 

Adenomata  are  clinically  benign.  The  greater  their  histological 
resemblance  to  normal  glands,  the  greater  their  maturity,  the  more 
benign  their  character.  They  grow  slowly  and  expansively.  But 
even  these  may  at  any  time  assume  more  active  proliferation  of 
their  glandular  elements.  These  more  and  more  rapidly  proliferat- 
ing cells  lose  then  their  typical  character  and  arrangement;  grow 
more  and  more  unrestrained  and  thus  develop  into  so-called  malig- 
nant adenomata  or  adenomatous  cancers.  In  them  the  tubular 
arrangement  may  be  still  preserved,  but  is  very  atypical;  the 
tubules  remain  incomplete,  without  definite  basement  membrane, 
produce  new  offsprings  before  they  themselves  are  fully  developed, 
and  infiltrate  surrounding  tissues  (malignant  adenoma,  adenoma 
desturens).  Epithelial  cells  may  also  proliferate  excessively  beyond 
tubular  linings  so  as  to  encroach  upon  and  fill  the  tubular  lumen 
(adenomatous  cancers,  see  below). 

(c)  Cystadenomata  (Cystomata).  The  genuine  cystic  tumors 
must  be  distinguished  from  those  growths  in  which  softening  and 
liquefaction  have  occurred  (pseudocysts)  or  from  otherwise  nor- 
mal glandular  organs  in  which  old  acini  have  been  distended  by 
retention  of  their  own  secretions  (retention  cysts).  The  true 
cystomata  are  glandular  tumors  (adenomata)  whose  lumina  are 
gradually  dilated,  and  occasionally  fuse  through  atrophy  of  their 
walls  by  accumulation  of  secretions  in  newly  formed  glands.  This 
gland  ectasy  depends  upon  pressure  of  the  fluid  and  elasticity  of 
gland  walls  which  allows  expansion.  The  cysts  are  lined  by  cuboid, 
cylindrical,  goblet-celled  or  flattened  epithelium.  The  individual 


CHANGES  IN  LOCAL  CELL  RELATIONS          275 

cysts  which  make  up  the  tumor  vary  much  in  size  and  shape.  They 
may  be  circular,  globular  or  irregular.  The  growth  and  traction  of 
the  surrounding  connective  tissue  stroma  is  apt  to  produce  bizarre 
shapes.  Fusion  from  tears  in  attenuated  cyst  walls  also  modifies  the 
shape  and  size.  Grossly,  cystic  tumors  are  thus  either  small  cystic, 
porous,  spongy  or  larger,  globular,  sometimes  solitary.  Cystic 
contents  are  generally  thin,  clear  and  colorless,  but  all  gradations  to 
thick,  colloid,  yellow  or  brownish  masses  are  found.  Hemor- 
rhages into  cyst  cavities  are  frequent. 

Cysts  may  be  simple,  that  is,  their  walls  smooth  and  clear, 
or  papilliferous,  that  is,  beset  with  papillary  glandular  processes 
or  projections  extending  into  and  growing  and  floating  in  the  cyst 
lumen.  These  papillary  projections  are  sometimes  sufficient  to 
almost  fill  cyst  cavities  (cystoma  papilliferum) .  They  exhibit  a 
greater  proliferative  activity  of  the  lining  epithelium  and  may  in- 
filtrate and  transplant  themselves  into  surrounding  tissues.  Metas- 
tases,  however,  are  rare.  A  common  type  of  this  locally  malignant 
cystoma  is  found  in  the  ovary  and  may  transplant  itself  at  times 
over  the  whole  peritoneum.  Its  cystic  fluid  is  a  characteristic, 
gelatinous  mucoid  material  (pseudomucin).  Adenomata  and  cysto- 
mata  are  frequently  combined  in  one  tumor,  one  part  being  glandu- 
lar and  another  cystic. 

Some  of  the  cystomata  are  evidently  of  embryonic  derivation  or 
spring  from  embryonic  epithelial  malformations  or  displacements. 
For  this  reason  cysts  are  frequently  encountered  in  teratoid 
growths  (see  below),  and  in  the  ovary1  and  testicle;  they  are  rarer 
in  breast,  kidney,  liver  and  bladder.  The  cystic  growths  of  kidney 
(cystic  kidney)  and  liver  are  generally  congenital.  In  the  kidney 
they  depend  upon  embryonic  faults  in  development  of  secretory 
tubules  and  lack  of  proper  fusion  between  those  parts  which  are 
derived  from  the  nephrogenic  cord  (convoluted  tubules)  with  those 
which  are  derivatives  of  the  Wolffian  duct  (collecting  tubules,  renal 
pelvis,  ureter).  Atresia  of  tubules  follows  with  subsequent  cystic 
dilatation. 

In  the  liver  they  depend  upon  similar  interferences  with  the 

1  The  resemblance  in  some  of  the  papilliform  cystadenomata  to  chorionic  villi 
and  chorionic  cells  is  striking.  See  under  chorioepithelioma  and  teratomata, 
282,  287. 


276  GENERAL  PATHOLOGY 

intrahepatic  bile  duct  system  (atresia  of  aberrant  bile  ducts).  They 
may  be  numerous  and  form  many  cysts.  The  liver  tissue  between 
these  is  generally  fibrous  and  this  fibrous  tissue  carries  dilated  bile 
ducts  and  remnants  of  portal  vessels.  Some  authors  speak  of  con- 
genital cystadenomata.  Cystic  kidney  and  liver  occur  not  infre- 
quently side  by  side. 

B.  UNDIFFERENTIATED,  IMMATURE,  UNCOORDINATED,  GENER- 
ALIZING ORGANOID  TUMORS:  CANCERS,  CARCINOMATA.  The 
term  cancer  was  originally  applied  by  Galenus  to  certain  tumors  of 
the  breast  in  which  superficial  veins  appeared  much  swollen  and 
radiated  somewhat  like  the  claws  of  a  crab.  Later,  the  name  was 
extended  to  include  all  malignant  and  infiltrating  growths.  Our 
present  conception  of  cancer  as  an  epithelial  growth  was  established 
in  classic  researches  by  Waldeyer  and  Thiersch  only  in  the  eighties 
of  the  last  century.  Since  then  the  term  has  been  restricted  to  those 
immature  epithelial  tumors  which  exhibit  an  independent,  infil- 
trating and  metastasizing  manner  of  growth. 

Cancers,  like  other  organoid  tumors,  possess  an  epithelial  paren- 
chyma and  connective-tissue  stroma,  but  the  relation  of  the  two  is 
disturbed,  not  coordinated.  There  does  not  exist  a  regular,  joint 
and  typical  growth,  but  an  emancipation  of  epithelium  over  the 
other  tumor  constituents.  Thus,  for  example,  surface  epithelium 
leaves  its  position  and  grows  in  all  directions,  the  lining  epithelium 
of  glands  no  longer  respects  any  gland  arrangement  but  prolife- 
rates into  the  gland  lumen,  breaks  through  the  basement  membrane 
and  invades  the  supporting  stroma.  The  cancer  cells,  thus  set  free, 
enter  lymph  and  tissue  spaces,  infiltrate  the  normal  surrounding 
tissues  and  metastasize  in  regionary  glands  or  distant  organs  (see 
under  Metastasis).  The  atypical,  unrestrained,  restless  epithelial 
proliferation  is  everywhere  in  the  foreground.1 

The  relation  of  cancer  parenchyma  to  its  stroma,  therefore,  is 
very  variable.  Some  still  resemble,  more  or  less  closely,  glandular 
construction.  But  even  in  these  the  resemblance  is  very  incomplete. 
Perfect  tubules  or  acini  are  never  found,  organoid  construction  is 
only  indicated  and  abbreviated.  Proliferation  continues  before  any 

1  Cancer  cells  possess,  as  shown  many  years  ago  by  Carmalt,  ameboid 
motion. 


CHANGES  IN  LOCAL  CELL  RELATIONS          277 

part  even  approaches  maturity.  From  the  more  highly  organized 
cancers  transitions  exist  to  those  lowest  types  in  which  practically 
no  correlation  between  parenchyma  and  stroma  occurs.  In  these 
resemblance  to  normal  organization  can  no  longer  be  noted.  In 
the  more  highly  developed  cancers,  the  cancer  cells  retain  some 
morphological  and  functional  similarity  with  the  mother  cells. 
Thus  cancer  cells  derived  from  liver  cells  may  still  secrete  bile, 
cancer  cells  from  mucous  glands  still  secrete  mucus.  On  the  other 
hand,  in  the  entirely  immature,  wildly-growing  cancers,  the  devia- 
tion from  the  original  cells  may  be  so  great  as  to  bear  no  resem- 
blance to  each  other.  In  these  tumors  the  manner  of  growth  is 
quite  unlike  normal  adult  tissue,  but  entirely  embryonic  in  solid 
nests,  cords,  columns,  surrounded  by  a  variable  amount  of  stroma. 

Cancer  cells  degenerate  frequently,  undergoing  mucoid  and 
colloid  degenerations,  those  arising  from  squamous  cells  become 
horny  and  keratinize  to  concentric  so-called  cancer  pearls. 

The  connective-tissue  stroma  of  cancer  shows  quantitative  and 
qualitative  differences.  It  is  either  abundant,  thick,  fibrous,  often 
hyaline  ( scirrhus  cancer),  giving  to  the  growth  the  appearance 
and  consistency  of  scar  tissue,  or  soft,  fibrillar  and  cellular  (soft 
medullary  cancer).  The  stroma  not  infrequently  becomes  inflamed 
and  calcified.  It  may  also  undergo  partial  metaplasia  to  cartilage 
or  bone.  In  some  rare  instances  the  stroma  joins  the  epithelium 
in  immature,  unrestrained  growths,  thus  establishing  a  combined 
cancer  and  sarcoma  (carcinosarcoma). 

The  origin  of  the  connective-tissue  stroma  and  its  relations  to 
the  epithelial  growth  have  been  much  discussed.  In  a  number  of 
early  cancers  it  is  clearly  demonstrated  that  the  connective  tissue 
follows,  and  grows,  in  one  way  or  another,  with  the  epithelial 
advance;  it  is,  therefore,  dependent  upon  it,  but  its  occasionally 
excessive  overgrowth,  such  as  in  the  scirrhus,  which  may  be  suffi- 
cient to  mask  in  parts  the  cancer,  is  difficult  to  account  for.  When 
cancers  take  origin  in  dislocated  epithelial  islands  embedded  in 
thick  old  scar  tissue,  such  as  from  old  healed  ulcers  or  fibrous 
inflammations,  much  of  that  connective  tissue  is  originally  old, 
inflammatory,  cicatricial  and  it  may  be  that  this  connective  tissue 
more  easily  responds  to  a  new  irritant.  Interesting  in  this  con- 
nection is  the  fact  that  metastases  from  scirrhus  cancers  are 


278  GENERAL  PATHOLOGY 

often  more  cellular,  less  fibrous  than  the  original.  Very  interesting 
growths  are  combined  sarcomata  and  carcinomata,  or  carcinosar- 
comata.  Borst  distinguishes  here  between  three  possibilities: 

First,  side  by  side  and  independent  occurrences  of  cancer  and 
sarcoma  in  one  locality  with  occasional  growth  of  one  into  the  other 
(combination  tumors). 

Second,  genuine  carcinosarcomata :  (a)  Simultaneous  cancer  and 
sarcoma  development  in  one  tumor.  (6)  Primary  cancer  with  second- 
ary sarcomatous  transformation  of  its  stroma.  Such  tumors  occur 
in  the  uterus,  ovaries,  thyroid,  breast,  intestinal  tract,  gall  bladder, 
nares  and  esophagus.  In  a  recent  case  observed  by  me  in  the  breast, 
the  growth  of  sarcoma  (large  spindle  cells)  took  origin  from  the 
connective  tissue  of  a  scirrhus  cancer,  and  cancer  and  sarcoma 
formed  two  fairly  well-defined  and  independent  tumor  masses  in 
one  and  the  same  growth. 

Very  rare  is  a  cancerous  development  from  epithelial  contents 
in  a  sarcoma.  Coenen  speaks  of  these  tumors  as  mutation  growths. 

Third,  false  or  pseudo-carcinosarcomata,  when  a  cancer  assumes 
a  more  diffuse,  histoid,  sarcoma-like  manner  of  growth.  This  occurs 
in  cellular,  medullary  cancers,  especially  in  metastases  or  trans- 
plants and  does  not  represent  a  transformation  of  cancer  into 
sarcoma  as  once  believed  by  some  investigators,  but  only  an 
unusual  morphological  expression  of  a  cancerous  growth.  These 
types  have  been  frequently  observed  in  experimental  transplants 
of  mice  cancers.  Borst  suggests  for  these  the  name  of  carcinoma 
sarcomatodes  (sarcoma-like  growing  cancer). 

All  cancers  develop  from  preexisting  epithelium,  either  direct, 
or,  by  transitions  from  a  mature,  benign  epithelial  growth  (ade- 
noma, papilloma,  cystoma). 

Glandular  cancers  grow  diffusely  and  massively  and  infiltrate 
affected  organs  and  surroundings.  Scirrhus  cancers  are  apt  to 
remain  better  confined  but  attach  themselves  by  adhesion  to  sur- 
rounding parts  (skin,  parenchymatous  organs,  stenosed  lumina), 
early  involve  glands  and  often  metastasize  so  extensively  as  to 
overshadow  the  small  original  growth  (cancers  of  breast  and  stom- 
ach). Cancers  from  skin  and  mucous  membranes  grow  as  papillary 
infiltrating  tumors  and  generally  are  apt  to  break  down  and 


CHANGES  IN  LOCAL  CELL  RELATIONS          279 

ulcerate  with  deep  defects  (ulcus  rodens).  The  base  and  edges 
of  such  ulcers  are  raised,  firm  and  show  cancer  extension.  Even 
hard  scirrhus  cancers  may  show  breaking  down  of  the  central  more 
cellular  parts  while  the  periphery  advances  hard  and  firm  (cancer 
en  cuirasse). 

Cancers  are  frequently  solitary  in  the  beginning,  but  occasionally 
of  multiple  origin  and  even  of  different  kinds  (combination  of  squa- 
mous-cell  cancer  of  the  skin  and  cylindrical  cancer  of  stomach,  etc.). 

Cancer  is  essentially  a  disease  of  advanced  age  (maximum  be- 
tween 50  and  60  years)  and  of  epithelial  regression.  Women  are 
especially  predisposed  in  their  sexual  organs  during  the  period  of 
physiological  senescence  after  the  menopause.  Epithelial  organs 
which,  like  the  pylorus,  rectum,  etc.,  are  much  exposed  to  wear 
and  tear  from  physical  and  chemical  irritations,  are  also  very 
liable  to  it. 

The  tempo  of  cancer  growth  varies  much  and  depends  upon 
many  circumstances  in  growth  and  surroundings.  Generally 
speaking,  glandular  cancers  grow  more  rapidly  and  metastasize 
more  frequently  than  those  from  skin  or  squamous  epithelial 
linings.  Glandular,  internal  cancers  lead  more  frequently  to  a  char- 
acteristic cancer  cachexia,  a  sort  of  chronic  intoxication  possibly 
due  to  perverse  functional  activity  (secretion)  of  cancer  cells.  The 
cancer  cachexia  must  not  be  confounded  with  the  anemia  and 
interferences  with  nutrition  which  are  due  to  a  particular  location 
of  the  tumor  (esophagus,  stomach,  gut). 

Types  oj  Cancer.  It  has  already  been  stated  that  all  cancers 
take  origin  either  from  surface  or  from  glandular  epithelium.  Con- 
sequently, cancers  may  be  divided  into:  (I)  Derivatives  from  sur- 
face epithelium.  (II)  Derivatives  from  glandular  epithelium. 

I.  Surface  Carcinomata:  (i)  Squamous  Cell  Cancers  (Epitbe- 
liomata).  These  occur  on  the  external  skin  or  other  surfaces  lined 
by  squamous  epithelium  (tongue,  esophagus,  larynx,  bladder,  cervix, 
etc.)  in  the  form  of  more  or  less  extensive  ulcerating,  flat  or  papil- 
lary and  fungoid  growths.  Two  types  may  be  distinguished,  first, 
a  tumor  consisting  of  solid  branching  cords,  nests  and  columns 
of  more  or  less  mature  squamous  epithelium  held  together  by  a 
fibrous  stroma.  The  epithelium  is  often  hyaline  and  tends  to  kera- 


28o  GENERAL  PATHOLOGY 

tinization  with  formation  of  characteristic  pearls  (cancroids).  This 
is  a  slowly,  but  progressively,  growing  tumor,  metastasizing  into 
regionary  glands,  but  not  further,  and  breaks  down  and  easily  be- 
comes infected.  Second,  a  tumor  consisting  of  immature,  rather 
atypical  embryonic  cells  with  no  tendency  to  keratinization  and 
much  less  accurate  reproduction  of  epidermis.  Cells  resemble  here 
the  deeper  (basal)  germinative  cells  of  the  lining  epidermis  and  have, 
therefore,  been  termed  basal-cell  cancers.  Here  the  epithelial  cells 
remain  less  differentiated  and  sometimes  assume  a  cylindrical,  al- 
most spindle-cell  shape  as  they  push  along  into  deeper  tissues  within 
lymph  and  tissue  spaces.  Thus,  microscopically,  extremely  delicate, 
finely  branching,  arborescent  epithelial  figures  appear  which 
differ  from  the  nodular,  coarser,  more  massive  progress  of  the 
squamous  cancers. 

For  these  reasons  it  has  been  doubted  that  these  tumors  are 
really  epithelial,  cancerous.  Some  have  regarded  them  as  endothe- 
liomata  (see  later)  taking  origin  from  the  lymph  endothelium. 
However,  the  occasional  intimate  combination  of  both  types 
and  their  connection  with  the  epithelium  of  the  skin  appendages 
(hair,  sebaceous  glands)  make  it  probable  that  they  are  epithelial, 
representing  cancer  cells  which  have  never  fully  developed  to  squa- 
mous types.  This  second  type  is  especially  prone  to  early  ulcera- 
tion  and  a  very  slow  and  persistent  progress.  It  forms  the  majority 
of  the  so-called  rodent  ulcers  of  the  skin  (face).  Squamous-cell 
cancers  may  take  origin  by  metaplasia  from  other  types  of  epithe- 
lium, more  especially  from  the  closely  related  ciliated  epithelium 
(gall  bladder,  uterus,  sometimes  stomach). 

2.  Cylindrical-cell  Cancers.  These  take  origin  from  surfaces 
normally  lined  by  cylindrical  epithelium:  gastro-intestinal  tract, 
respiratory  organs  (bronchi),  bile  ducts  and  gall  bladder.  They  are 
often  polypoid.  The  cylindrical  cells  lie  in  nests,  alveoli  or  tubular 
spaces  within  a  stroma  and  fill  their  lumina.  They  also  cover  the 
surfaces  of  projecting  papillae.  In  some  more  highly  developed 
forms  a  somewhat  glandular  arrangement  into  cylinders  is  visible 
(cylindroma).  Some  of  these  tumors  may  take  origin  from  em- 
bryonic epithelial  remnants  such  as  from  branchial  clefts  and  re- 
mains of  the  tail. 


CHANGES  IN  LOCAL  CELL  RELATIONS          281 

II.  Glandular  Carcinomata.  These  originate  from  glands  and 
imitate  gland  structure  (C.  adenomatosum).  Here  acini  are  formed, 
but  without  basement  membrane,  and  they  are  lined  by  several 
layers  of  cuboid,  cylindrical,  undifferentiated  epithelium  which  re- 
tains a  secretory  activity  (mucus,  etc.).  Some  still  possess  an  adeno- 
matous  character,  the  epithelium  may  even  restrict  itself  to  a  single 
lining  of  acini  or  tubules,  but  they  are  formed  excessively,  incom- 
pletely and  are  unrestrained  in  their  arrangement  and  growth. 
This  similarity  to  adenomata  and  the  restriction  of  epithelial  pro- 
liferation to  lining  of  the  tubules  has  led  to  a  separate  classification 
as  malignant  adenoma  or  adenoma  destruens.  In  others,  however, 
the  adenomatous  character  is  coupled  with  excessive,  unrestrained 
epithelial  proliferation  which  encroaches  upon  the  lumen  and 
breaks  at  various  points  to  the  outside.  These  are  true  adenocar- 
cinomata.  They  are  frequently  occurring,  malignant  tumors  of  all 
the  internal  glandular  organs.  They  often  undergo  degeneration 
(mucoid,  colloid)  and  may  metastasize  extensively,  especially  in 
the  liver. 

Finally,  there  are  the  true  cancers  in  the  restricted  sense,  resem- 
bling the  earliest  embryonic  gland  formations  with  undifferentiated 
epithelial  cells.  They  grow  as  solid  cell  cords  or  alveoli.  Occasion- 
ally the  solid  epithelial  cords  show  some  attempts  at  canalization, 
(aciuns  formation)  but  it  always  remains  quite  incomplete,  and 
these  tumors  are  embryonic  throughout.  They  carry  much  or  little 
stroma,  and  are,  therefore,  either  hard  or  soft.  Such  growths  not 
infrequently  take  origin  from  old,  atrophied,  degenerated  paren- 
chyma cells,  isolated  and  in  a  new  environment  of  inflammatory 
or  regressive  changes.  While  a  certain  number  of  glandular  cancers 
are  derived  from  epithelial  parenchyma,  the  ducts  may  also  give 
rise  to  cancers  and  these  reproduce  incomplete  ducts  (duct  cancers). 

SPECIAL    TUMORS    OF    EPITHELIAL   GLANDULAR   TISSUE 

i .  HYPERNEPHROMA.  Under  this  name,  or  as  struma  suprarenalis 
aberrata,  is  grouped  a  type  of  tumors  which  closely  imitate  the 
tissue  of  the  suprarenal  gland,  especially  of  its  cortex.  They  are 
found  in  the  suprarenal,  but  very  frequently  also  in  the  kidney.  They 
present  a  characteristic  soft,  yellow  fatty  appearance  and  were 


282  GENERAL  PATHOLOGY 

formerly  regarded  as  renal  lipomata  until  Grawitz  demonstrated 
the  close  similarity  in  cell  character  and  arrangement  of  these 
growths  and  the  cortex  of  the  suprarenal  gland.  Since  then  it  has 
been  generally  believed  that  they  arise  in  the  kidney  from  aberrant 
suprarenal  rests  which  during  embryonic  development  have  been 
included  within  the  kidney.  These  tumors  grow  either  in  a  more 
typical,  benign,  or  atypical,  malignant  manner  in  which  case  they 
display  a  great  tendency  to  break  massively  into  veins  and  thus 
metastasize  in  lungs,  brain,  liver,  and  frequently  in  bones.  They 
are  very  vascular,  exhibit  great  tendency  to  hemorrhages  and  show 
in  section  a  characteristic  mottled  appearance. 

Microscopically,  cells  grow  in  the  typical  tumors  in  the  form 
of  well-arranged  columns  and  tubules  which  are  separated  by  thin 
vascular  septa,  in  the  atypical  forms  only  aborted  acini  or  tubules 
are  seen,  the  epithelium  grows  irregularly,  excessively  (carcinoma- 
tous)  and  occasionally  in  cystic  or  papillomatous  fashion.  The  cells 
are  generally  large,  fatty  or  rich  in  glycogen.  Some  of  these  tumors 
lose  their  epithelial  character  almost  entirely,  revert  to  primitive 
mesothelial  cell  (see  under  Endotheliomata)  and  become  more 
sarcomatous. 

The  recent  researches  of  Stoerk  and  others  have  made  it  doubtful 
whether  a  large  number  of  tumors  of  the  kidney  regarded  as 
hypernephromata  are  really  of  suprarenal  origin,  but  that  they  are 
rather  true  renal  cancers.  Early  in  embryonic  life  cells  from  the 
nephrogenic  cord  may  remain  isolated  and  undifferentiated  and 
later  develop  in  a  manner  which  closely  resembles  suprarenal  cells. 
Pictures  may  be  noted  in  some  instances  which  strongly  suggest 
relation  of  the  tumor  to  renal  cells  and  construction,  and  transi- 
tions to  the  "suprarenal"  type.  The  investigations  of  Crowdy  have 
also  shown  that  even  in  other  glandular  cancers,  as  for  example  in 
the  breast,  very  similar  fatty  and  glycogen  infiltrations  of  cancer 
cells  may  occur  and  may  imitate,  sometimes  in  the  most  perplexing 
manner,  the  typical  hypernephromata. 

2.  CHORIOEPITHELIOMA.  A  very  malignant  destructive  tumor 
arising  during  or  after  pregnancy  from  the  fetal  chorion  and  grow- 
ing in  unrestricted  tumor  fashion  into  the  mother.  This  growth  is 
extremely  interesting  as  an  illustration  of  tumor  formation  from 


CHANGES  IN  LOCAL  CELL  RELATIONS          283 

exaggeration  of  a  normally  restricted  physiological  performance. 
Chorionic  villi  (fetal  ectoderm)  are  the  fetal  contribution  to  the 
placenta,  while  the  maternal  part  comes  from  the  decidua  serotina. 
Even  under  normal  conditions  cells  of  chorionic  villi  grow  into  the 
maternal  mucous  membrane  and  erode  maternal  vessels.  From 
these  blood  extravasates  and  forms  the  intervillous  spaces  which 
separate  maternal  and  fetal  tissue.  Later,  the  villi  increase  and 
float  in  maternal  blood.  Thus,  an  intervillous  circulation  is  estab- 
lished and  fetal  and  maternal  parts  unite  to  form  the  placenta. 
It  follows  that  even  normal  placentation  shows  an  advance  and 
invasion  by  embryonic  cells  into  maternal  tissue  and  these  cells 
may  even  enter  the  general  circulation  in  moderate  numbers,  lodge 
and  embolize  in  blood  vessels  of  the  liver  and  lung,  probably  also 
elsewhere,  but  grow  no  further,  and  disintegrate.*  Under  certain 
conditions,  however,  chorionic  cells  (Langhans'  pale,  vesicular  cells 
as  well  as  syncytium)  continue  to  grow  and  advance,  and  develop 
into  a  destructive  and  metastasizing  malignant  cancerous  tumor. 
They  penetrate  massively  into  the  uterine  wall,  into  veins,  and 
appear  as  true  tumor  metastases  in  distant  organs  (lungs,  etc.). 
The  tumors  show  microscopically  either  a  more  typical  chorionic 
structure  in  which  both  cell  layers  combine  or  a  very  irregular 
atypical  structure  of  syncytial  masses  and  interpolated  large,  pale 
Langhans'  cells.  Occasionally,  the  tumor  infiltration  may  not  be 
noticeable  in  the  placenta  itself  but  appears  extraplacental  and 
in  the  vagina  and  other  organs  months  after  delivery. 

The  tumor  was  first  carefully  described  and  studied  by  Sanger, 
who  regarded  it  as  decidual  in  origin  (deciduoma  malignum),  that 
is,  sarcomatous.  The  subsequent  elaborate  researches  of  Marchand 
established  its  epithelial,  chorionic  derivation,  which  is  generally 
now  accepted.1 

III.    ENDOTHELIOMATA 

INTRODUCTION.  The  tumors  of  endothelial  derivation  hold  a 
special  position.  For  just  as  endothelium  is  histologically  and  em- 
bryologically  derived  from,  and  at  the  same  time  closely  related 

1  Chorioepitheliomata  and  similar  growths  are  sometimes  to  be  observed  in 
teratomata  (see  below)  and  in  other  tumors  of  sexual  organs  (ovary,  testicles). 
(Imitations  of  fetal  ectoderm.) 


284  GENERAL  PATHOLOGY 

to,  the  connective  tissues  and  epithelium,  so  endothelial  tumors 
stand,  as  it  were,  between  histoid  and  organoid  growths.  In  certain 
instances  they  resemble  the  former  in  formation  of  vascular  tissues, 
in  other  cases  they  approach  organoid  construction  through  growth 
of  epithelial-Iike  cells  which  lie  in  and  are  connected  by  a  fibrous 
stroma.  These  peculiarities  of  dualistic  character  are  due  to  the 
position,  derivation  and  development  of  the  mesoderm  from  which 
endothelium  is  derived.  Mesoderm  comes  to  lie  between  ectoderm 
and  entoderm,  both  of  which  contribute  towards  its  formation. 

Subsequently  the  mesoderm  splits;  one  part  differentiates  to  full 
secretory  epithelium  of  certain  glandular  organs  (kidney,  uterus) ; 
another  develops  into,  and  lines,  the  body  cavities.  This  lining 
endothelium  appears  and  behaves  much  like  epithelium  (meso- 
thelium).  The  rest  of  the  mesoderm  remains  at  a  lower  stage  of 
differentiation.  It  forms  a  cell  mass  around  a  central  canal  and 
ultimately  goes  to  form  heart  and  blood  and  lymph  vessels.  These, 
finally,  are  lined  by  a  layer  of  cells,  the  endothelium  of  the  circula- 
tory system,  which  retains  throughout  a  mesodermal  character. 

Consequently,  tumors  arising  from  mesothelium  grow  in  a  more 
organoid  epithelial  fashion,  while  those  arising  from  the  vascular 
tube  are  generally  histoid  in  character. 

A.  HISTOID  OR  VASCULAR  ENDOTHELIOMATA.  Angiomata  are 
tumors  in  which  the  formation  of  blood  or  lymph  vessels  constitutes 
the  essential  character  of  the  growth.  They  develop  by  budding  of 
endothelial  cells  from  an  originally  normal  focus  or  more  frequently 
from  an  embryonic  faulty  over-production  of  blood  or  lymph 
vessels  in  a  part  (hamartomata).  The  mature  angiomata  show  more 
or  less  fully  developed  vessels,  surrounded  and  held  together  by 
a  greater  or  lesser  amount  of  connective  tissue.  The  fibrous  stroma 
may  be  so  abundant  and  exert  so  much  traction  on  the  vessels  that 
these  dilate  to  large  sinuses  (fibroangiomata).  Sometimes  the 
stroma  grows  into  the  lumen  of  the  vessels  in  papillary  projections. 
Interesting  is  the  occasional  intravascular  growth  of  angiomata 
within  old  blood  vessels,  as  in  the  portal  vein.  Angiomata  may  be 
subdivided  into  hemangiomata  and  lymphangiomata: 

(a)  Hemangiomata.  These  are  either  simple  or  cavernous. 
The  simple  type  is  frequent  in  the  skin  as  vascular  moles  or  birth- 


CHANGES  IN  LOCAL  CELL  RELATIONS          285 

marks  and  are  generally  hamartomata  (excess  of  blood  vessels). 
They  consist  of  capillaries,  arteries  and  veins.  Their  favored  seats 
are  skin,  liver,  spleen  and  kidney.  AH  sorts  of  transitions  between 
mature  types  and  more  actively  growing,  cellular,  sarcomatous  or 
malignant  forms  (angiosarcomata)  occur. 

(b)  Lymph angiomata.     These  closely  resemble  the  hemangiomata 
and  like  them  are  often  hamartomata  or  only  dilatation  or  ectasy 
of  old  lymph  spaces  which  makes  them  conspicuous.  They  are 
frequent  in  skin  and  sometimes  are  found  in  viscera.  Interesting  is 
an  occasional  combination  with  lipoma.  Congenital  lymphangiec- 
tasis  is  found  in  the  cutis  and  subcutis  and  consists  of  an  endothelial 
hyperplasia  growing  into  the  papillary  body  in  the  form  of  cell  nests. 
Occasionally  they  appear  in  cystic  form  (skin  of  neck  and  back) 
and  are  covered  by  the  lining  epidermis  (Hygroma  cysticum). 
They  have  also  been  observed  in  the  mesentery.  The  true  lymph- 
angiomatous  tumors  arise  from  these  congenital  hamartomata. 

(c)  Angiosarcomata.     When  the  endothelial  cells  of  angiomata 
assume  greater  activity  and  newly  formed  vessels  remain  incom- 
plete, aborted,  or  when  these  cells  only  attempt  to  unite  to  vessels, 
and  grow  more  or  less  diffusely  and  undifferentiated,  we  speak  of 
them  as  angiosarcomata.  Here  endothelial  cells  are  no  longer  re- 
stricted to  the  lining  of  mature  vessels,  but  grow  between  them, 
into  them  and  occasionally  surround  a  lumen  in  cylindrical  sheaths 
of  several  cell  layers  (sarcoma  perivasculare,  or  perithelioma) . 
Cells  are  less  typical  endothelial,  sometimes  even  elongated.  Care 
must,  however,  be  exercised  in  the  differential  diagnosis  of  these, 
for  other  rapidly  growing,  undifferentiated  tumors  occasionally 
imitate  a  similar  perivascular  arrangement. 

Occasionally  a  very  intimate  contact  and  mixture  of  tumor  and 
blood  cells  is  brought  about  and  pictures  occur  which  strongly 
suggest  transformation  of  tumor  into  blood  cells,  or  embryonic 
intra-  and  extravascular  blood  formation.  These  growths  are  infil- 
trating, metastasize  by  blood  stream  and  have  a  nodular,  or  globu- 
lar and  deeply  red  appearance. 

B.  ORGANOID  ENDOTHELIOMATA  (MESOTHELIOMATA)  (From 
lining  endothelium  of  body  membranes).  Mature,  localized, 
benign  organoid  endotheliomata  are  known  only  in  the  dura  mater 


286  GENERAL  PATHOLOGY 

and  soft  meninges.  They  exhibit  great  tendency  to  calcification 
(psammoma).  The  calcium  is  deposited  in  spicules  and  bars  in 
connective  tissue.  Even  blood  vessels  may  calcify. 

The  vast  number  of  organoid  endotheliomata  are  of  immature, 
infiltrating  and  metastasizing  character.  They  are  not  infrequent 
in  the  pleura,  rarer  in  the  peritoneum.  Microscopically,  they  pre- 
sent nests  of  flat,  epithelial-Iike  cells  separated  by  a  dense  connect- 
ive tissue  stroma,  much  like  the  scirrhus;  sometimes  they  are  cellu- 
lar. They  grow,  infiltrate  and  metastasize  by  lymph  channels.  The 
cells  are  small  or  large,  flat,  sometimes  high,  almost  cylindrical,  or 
clear  and  serous,  grouped  in  an  acinar  construction  resembling 
mucous  glands  (danger  of  confusion  with  true  cancers).  They  gen- 
erally transform  a  whole  serous  membrane  into  a  thick,  pearly 
white,  cartilaginous  coat,  giving  the  first  impression  of  a  product- 
ive fibrous  inflammation.  In  this  tissue  may  be  found  cystic  areas 
filled  with  clear  fluid  (endothelial  secretion).  But  the  narrowed 
original  serous  cavity  is  usually  filled  with  dark  hemorrhagic  fluid 
which  may  contain  tumor  cells. 

Metastases  from  these  tumors  may  revert  still  further  in  dif- 
ferentiation to  sarcoma-like  cells  and  manner  of  growth. 

IV.  MIXED,  EMBRYONIC  TUMORS  OF  DEVELOPMENTAL 
DERIVATION 

By  the  term  teratomata  (repas  =  monster),  or  teratoid  growths, 
we  understand  tumors  whose  parenchyma  is  derived  from  several 
layers  of  the  blastoderm  and  which  develop  either  to  an  indifferent 
embryonic  mixture  of  tissues  inserted  within  normal  organs,  or 
advance  to  an  organ-like  independent  construction  within,  or 
attacked  to,  the  host. 

All  these  tumors  take  origin  from  cells  which  have  been  isolated 
from  general  development  or  have  migrated  into  other  tissues  early 
in  embryonic  life.  From  such  undifferentiated,  multipotential 
cells,  representing  one,  two  or  all  three  layers  of  the  blastoderm, 
mixed  tumors  arise,  and,  depending  upon  the  potency  at  time  of 
separation  and  the  environment  within  which  they  are  placed, 
develop  into  tissues,  organs  and  even  partial  or  whole  embryos 
which  are  attached  to  the  fully  developed  individual.  The  manner 


CHANGES  IN  LOCAL  CELL  RELATIONS          287 

and  type  of  development  in  the  misplaced  or  immigrated  cells  is, 
therefore,  dependent  upon  the  potential  contents  of  the  misplaced 
cells  and  upon  environmental  influences.  For  it  is  well  established 
that  embryonic  cells  in  abnormal  situations  differentiate  them- 
selves abnormally  and  display  greater  potencies  than  under  normal 
conditions.  As  Hans  Driesch  puts  it,  "The  prospective  potencies 
of  cells  are  greater  than  their  prospective  importance." 

Thus  it  happens  that  some  teratoid  growths  show  not  only  iso- 
lated, independent,  abbreviated  development  of  embryonic  cells, 
but  actual  misdirection.  This  is  the  case,  for  example,  in  the  mixed 
growths  of  the  kidney  and  in  cystic  kidney  in  which  the  meso- 
dermal  cells  of  the  nephrogenic  cord  revert  to  connective  tissue, 
muscle  and  cartilage  instead  of  normal  evolution  to  epithelium. 
A  similar  misdirection  of  growth  occurs  in  teratomata  of  lungs  and 
other  organs. 

A.  TERATOID  (HISTOID)   GROWTHS.     In  the  teratoid  growths' 
mixtures  of  simple  embryonic  tissues  occur  without  organoid 
arrangement  or  attempt  at  organ  formation.  These  tissues  are  of 
connective  tissue  and  epithelial  derivation  and  produce  their  type 
more  or  less  faithfully.  They  occur  in  all  parts  of  the  body;  in 
the  lungs  as  growths  of  muscle  tissue,  cysts  or  epithelial  tubes;  in 
the  breast  as  epidermal  cysts;  in  the  kidney  in  form  of  aborted 
tubules   embedded    in   fibroplastic,    immature   connective  tissue 
(adenosarcoma),  or  as  cystic  sarcomata.  They  are  especially  fre- 
quent in  parts  in  which  embryonic  development  is  complicated 
such  as  in  the  pharynx  and  parotid  region.  Here  are  frequently 
found  tumors  of  endothelial  lymph  and  blood  channels,  mucoid 
tissue,   cartilage,   bone  and  remains  of  bronchial  clefts.  These 
growths  may  remain  local  or  assume,  as  a  whole  or  in  parts,  a 
malignant  character. 

B.  TERATOMATA.     In  the  true  teratomata  occur  derivatives  of 
all  three  layers  of  the  blastoderm  in  organ-like  reproductions. 
Such  tumors  present  a  more  or  less  complete  reproduction  of  skin, 
nervous  tissue,  skeleton,  respiratory  organs,  teeth,  even  abbre- 
viated glandular  organs:  lung,  kidney,  thyroid  and  cystic  tissue. 
Teratomata  show  generally  uneven  development,  better  in  some 
than  in  other  parts.  The  most  common  representative  of  this  class 


288  GENERAL  PATHOLOGY 

is  the  dermoid  cyst  in  skin  and  ovaries:  a  large  central  cyst  lined 
by  skin,  filled  with  sebaceous  material  and  to  the  wall  of  which  are 
attached  hair  and  teeth.  Occasionally  these  cystic  teratomata  are 
more  complicated  and  contain  a  tongue,  parts  of  respiratory  sys- 
tem and  digestive  organs.  The  teratomata  occur  with  predilection 
in  the  sex  organs,  but  are  also  found  in  bladder,  rectum,  breast, 
mediastinum  and  elsewhere.  As  in  teratoid  growths  they  may  take 
on  malignant  properties  either  in  parts  or  as  a  whole.  Microscopic 
demonstration  of  this  phenomenon  is  not  always  possible  from  sec- 
tion because  embryonic  undifferentiated  cell  character  is  here 
no  proof  of  malignancy.  Diagnosis  must  be  made  from  biological 
behavior  of  diffuseness  in  growth,  infiltration  and  metastases. 

C.  EMBRYOMATA.  Embryomata  are  complex,  more  fully  devel- 
oped teratomata  which  really  represent  an  abbreviated  twin  at- 
tached in  one  or  the  other  part  to  a  well-formed  host.  These  arise 
from  totipotential  cells  which  have  been  isolated  from  their  con- 
temporaries at  a  very  early  period  of  embryonic  life  (blastomeres). 
In  blastomeres  germinal  and  somatic  plasma  is  still  mixed.  Gradu- 
ally the  sex  cells  free  themselves  by  repeated  division  from  somatic 
plasma  and  thus  become  sexual  blastomeres.  From  such  mixed 
somatic  and  sexual  blastomeres  embryomata  develop,  reproducing 
more  or  less  faithfully  a  parasitic  twin.  The  frequent  location  of 
attachment  is  the  sacrococcygeal  region  and  the  head  (epignathi, 
from  CTTI  =  on;  yvados  =  jaw).  Occasionally  they  are  attached  to 
the  jaw,  also  to  the  wall  of  the  abdominal  cavity  (fetus  in  fetu  per 
inclusionem) .  Here  the  parasite  which  is  contained  in  mem- 
branes is  attached  to  the  peritoneum  by  a  cord  (pseudo-navel 
cord). 

Such  embryomata  really  stand  on  the  borderline  of  true  twins. 
Wilms  regarded  these  growths  as  the  result  of  true  parthenogenesis 
of  ova,  but  there  is  so  much  against  this  possibility  in  higher  ani- 
mals that,  taken  in  connection  with  their  occasional  occurrence  in 
the  testicle  and  their  incomplete,  irregular,  abbreviated,  and  un- 
balanced manner  of  development,  this  view  has  been  dropped  by 
Wilms  himself  in  favor  of  Marchand's  and  Bonnet's  conception  of 
blastomere  derivation.  Be  that  as  it  may,  it  remains  an  important 
fact  that  tumors  and  tumor-like  malformations  and  inclusions 


CHANGES  IN  LOCAL  CELL  RELATIONS          289 

may  arise  from  cells  so  young  as  to  contain  the  material  for  all 
three  layers  of  the  blastoderm  and  that,  in  their  development,  cells 
and  tissues  from  one  or  the  other  layer  may  predominate  and 
assume  independent  growth. 

ETIOLOGY   AND   HISTOGENESIS   OF   TUMORS 

Etiology  and  histogenesis  of  tumors  are  still  the  most  obscure 
and  complicated  field  in  pathology.  Like  all  obscure  and  compli- 
cated problems  they  have  given  rise  to  many  hypotheses  and  theo- 
ries, some  sensational  and  entirely  speculative. 

We  must  confess  that  we  are  unacquainted  with  the  immediate 
causes  of  tumor  growth.  Nevertheless,  there  exist  certain  facts 
which  point  more  or  less  to  the  direction  in  which  the  solution  of 
the  problem  lies.  Let  us  examine  these  facts. 

First,  all  tumors  are  derived  from  the  cells  of  the  organism  from 
which,  and  upon  which,  they  grow.  The  ultimate  cause  of  tumor 
growth  must  lie,  therefore,  in  the  cells  themselves.  We  know  that 
tumor  growth  is  not  the  immediate  response  of  cells  to  outside 
(parasitic)  irritants,  as  in  the  inflammatory  lesions.  In  them,  cell 
proliferation  stands  in  immediate  relation  to  quantity,  location, 
and  time  action  of  the  irritant.  In  inflammatory  growth,  therefore, 
cell  proliferation  is  always  dictated  and  limited  by  these  outside 
factors  and  cell  growth  and  division  are  a  direct  response  to  an 
environmental  call. 

In  tumor  growth,  however,  no  such  direct  relation  of  environ- 
ment to  cell  activity  is  to  be  noted.  It  is  the  independence  of  the 
tumor  cell,  its  inherent  quality  to  grow  which  distinguishes  it  from 
others.  The  mature,  benign  tumors  show  it  in  lesser  degree,  the 
immature,  malignant  tumors  in  high  degree.  In  other  words,  the 
problem  in  all  types  of  tumor  growth  is  the  same:  what  is  the  cause 
of  cell  independence,  or,  what  causes  and  processes  lead  up  to 
their  independence? 

To  approach  this  question  properly  we  must  ask  first  in  what 
respects  tumor  cells  differ  morphologically  and  functionally  from 
their  physiological  antecedents. 

It  is  at  once  apparent  that  even  in  the  benign  mature  tumors  a 
complete  approach  to  physiological  cell  structure,  arrangement  and 

19 


290  GENERAL  PATHOLOGY 

function  is  never  quite  reached.  Certain,  sometimes  slight,  devia- 
tions in  appearance,  arrangement  and  function  are  always  present. 
These  put  the  tumor  cell  below  its  physiological  prototype;  a 
greater  or  lesser  resemblance  to  embryonic  cells  in  form  and  be- 
havior, therefore,  is  apparent.  But  here  this  difference  is  also  to 
be  noted:  The  tumor  cell  is  not  latent  in  its  qualities,  but  it  is  per- 
manently lowered  in  differentiation. 

With  this  lowered  morphological  differentiation  goes  loss  of 
higher  cell  functions.  This,  then,  is  the  most  important  character 
variation  in  tumor  cells  from  their  physiological  antecedents; 
strong  in  vegetative,  weak,  sometimes  perverse,  in  higher  func- 
tional expressions;  always  incomplete  and  unbalanced  in  differ- 
entiation. The  problem  of  tumor  growth,  therefore,  resolves  itself 
into  this  question:  "What  is  the  cause  of  loss  in  higher  differentia- 
tion and  function,  with  retention  of  elementary,  vegetative  attri- 
butes of  nutrition  and  growth?" 

In  the  answers  to  this  question  two  main  currents  of  thought 
are  noticeable.  The  first  assumes  that  the  tumor  character  in 
cells  is  entirely  dependent  upon  changes  in  cell  environment  and 
not  due  to  essential  changes  in  cells  themselves.  The  second 
assumes  that  all  tumor  growth  depends  upon  primary  cell  changes 
which,  while  removing  some  or  all  of  their  higher  differentiation 
and  functions,  endow  them  with  increased  powers  of  growth.  The 
first  current  of  thought  it  best  expressed  by  Cohnheim  and  Ribbert. 

Cohnheim  regarded  all  tumors  as  derivatives  of  embryonic  rests, 
that  is,  from  cells  which  have  been  isolated  from  the  general, 
coordinated  evolution  early  in  embryonic  life  and  which,  on  ac- 
count of  lack  of  continuity  and  coordination  with  surrounding 
structures,  assume  independence  and  grow  by  themselves. 

There  can  be  no  doubt  that  tumors  arise  from  embryonic  or 
dislocated  rests.  We  have  repeatedly  had  occasion  to  observe  this 
in  the  preceding  pages.  But  in  view  of  what  we  know  it  is  not  prob- 
able that  all  tumors  arise  in  this  fashion,  and  moreover  this  theory 
does  not  explain  why  these  rests  commence  to  grow  at  a  particular 
time,  sometimes  late  in  life,  and  what  determines  this  development 
in  one  case  to  mature,  benign,  and  in  another,  to  immature,  malig- 
nantltumors. 


CHANGES  IN  LOCAL  CELL  RELATIONS          291 

The  views  of  Ribbert  are  an  extension  of  Cohnheim's  ideas. 
Ribbert  does  not  restrict  the  origin  of  tumors  to  embryonic  dis- 
location of  cells  and  only  to  aberrant,  embryonic  rests,  but  believes 
that  any  post-natal  interference  with  cell  continuity,  such  as 
inflammatory  separation,  is  sufficient  to  set  the  always  present 
power  of  growth  in  cells  into  motion.  Thus,  in  chronic,  productive 
inflammations  of  the  skin,  the  connective  tissue  separates  epi- 
dermal epithelium  from  its  physiological  location,  these  cells  lose 
normal  contact  and  now  grow  in  vegetative  manner. 

It  will  be  admitted  that  dislocation  of  cells  from  their  normal 
location  and  introduction  into  foreign  environment  are  potent  fac- 
tors in  influencing  cell  life  and  may  aid  in  the  manifestation  of 
vegetative  attributes.  But  by  themselves  they  appear  unable  to 
initiate  it.  For  how  many  times  are  cells  dislodged  without  it?  To 
the  contrary,  evidence  indicates  that  ordinary  cells,  when  dis- 
located, generally  remain  isolated  and  inactive  and  disintegrate. 
Unless,  therefore,  dislocated  cells  possess  additional  characters  of 
tumor  cells,  they  do  not  continue  to  grow  and  form  new  tissue. 
Ribbert  himself,  in  his  later  publications,  admits,  therefore,  an 
additional  cell  reversion.  For  reasons  of  these  deficiencies  in  theo- 
ries which,  like  Cohnheim's  and  Ribbert's,  put  the  essential  weight 
on  cell  separation  alone,  investigators  have  concentrated  their 
attention  more  and  more  upon  certain  primary  changes  and  dis- 
turbances in  the  parent  tumor  cells. 

A  sharp  definition  of  these  internal  cell  alterations  was  intro- 
duced by  von  Hansemann  in  the  idea  of  anaplasia.  By  anaplasia 
(ava  =  backward,  TrXdo-o-ctv  =  to  form)  is  understood  a  descent 
or  regression  in  differentiation  and  a  corresponding  production 
of  less  differentiated  (tumor)  races  of  cells.  Others  have  used  the 
term  kataplasia  (Kara  =  down,  TrXatro-ct^  =  to  form).  By  morpholog- 
ical and  functional  regression  there  develop  one-sided,  unbalanced 
cells  in  which  vegetative  functions  control  and  which,  therefore, 
may  overgrow  and  replace  the  highly  organized,  vegetatively 
weaker,  physiological  cells.  Accepting  this  idea  as  self-evident  and 
as  a  general  expression  of  tumor  cell  characters,  the  most  important 
part  of  the  problem  still  remains  to  be  solved :  how  is  this  perma- 
nent loss  in  differentiation  and  higher  functions  brought  about? 


292  GENERAL  PATHOLOGY 

To  find  an  adequate  answer  to  this  question,  it  is  necessary 
first  to  inquire  into  the  conditions  of  tumor  growth  and  into  the 
processes  which  precede  tumor  development.  We  know  that  a  large 
number  of  tumors  arise  on  the  basis  of  long-continued  irritations  of 
more  or  less  specific,  infective,  chemical  or  physical  nature,  very 
rarely,  if  at  all,  after  acute  insults.  It  is  safe  to  assume  that  in  at 
least  the  majority  of  instances  these  irritations  have  extended  over 
a  long  time  and  produced  a  profound  influence  on  cell  character 
and  tissue  construction.  Thus,  for  instance,  cancer  of  the  skin  of 
the  abdominal  wall,  rare  with  us,  is  frequent  in  the  inhabitants 
of  Kashmere,  for  the  reason  that  a  warming  basket,  containing 
burning  charcoal,  is  carried  on  the  abdomen,  leading  to  repeated 
burning.  Moreover,  cancers  of  the  lip,  tongue,  pylorus,  rectum,  gall 
bladder,  etc.,  are  noted  especially  in  parts  which  are  exposed  to 
long-continued  mechanical,  chemical  and  infective  irritations  and 
degeneration  of  fixed  tissues. 

In  China,  where  men  eat  the  rice  first  and  very  hot,  cancer  of  the 
esophagus  is  very  frequent,  much  less  so  in  women,  who  eat  rice 
last  and  cold  (Bashford). 

In  regions  of  the  Upper  Nile  instances  of  melanotic  sarcoma  on 
the  sole  of  the  foot,  exposed  to  constant  injuries  in  the  barefooted 
population,  are  not  uncommon. 

Finally,  tumor  growths  arise  from  old,  unhealthy  scars,  X-ray 
exposures;  cancers  of  the  liver  from  aborted  regenerations  of  the 
liver  in  inflammations,  etc. 

But  quite  apart  from  these  chronic  inflammatory  irritations  we 
know  that  organs  undergoing  regression  and  senescence  are 
particularly  liable  to  tumor  growths.  Cancers  of  uterus  and 
breast  are  most  frequent  during  or  after  menopause  when 
physiological  functions  are  lost  and  involution  proceeds.  Often 
we  find  both  instances  combined,  i.e.,  cell  regression  associated 
with  chronic  irritation  (inflammation)  of  tissues.  Both  are  the 
preparators,  so  to  speak,  for  tumor  development.  Here  the 
morphological  and  functional  decline  is  combined  with  certain 
influences  which  develop  the  remaining  vegetative  attributes  to  a 
high  degree  of  activity.  Can  we  form  a  visual  conception  of  the 
manner  of  this  change? 


CHANGES  IN  LOCAL  CELL  RELATIONS          293 

In  order  to  do  this  we  must  recall  certain  phenomena  of  cell 
life.  All  cell  life  and  all  cell  functions  are  intimately  connected 
with  the  nucleus  and  nucleus-plasma  relations.  The  nucleus  is,  in 
higher  metazoa,  not  a  uniform,  qualitatively  equal  structure,  but 
rather,  as  we  saw  in  the  discussion  of  heredity,  a  complex  organic 
union  of  chromosomes  which  stand  in  direct  relation  to  sex,  hered- 
itary unit  characters  and  cell  functions.  The  higher  the  cell  the 
greater  and  more  complex  the  union  of  chromosomes.  In  lower 
cell  life  these  structures  have  not  yet  permanently  fused  to  one 
nucleus,  but  still  exist  separately  in  two  nuclei,  a  vegetative  and  a 
functional  nucleus  which  control,  the  one,  nutrition  and  growth,  the 
other,  the  functional  activities  of  the  cell.  As  we  ascend  in  the  ani- 
mal scale  a,  first  temporary,  then  permanent,  fusion  and  further 
differentiation  of  these  two  chromosome  types  occur.  Thus  re- 
sults a  complex  nuclear  unit,  standing  in  definite  relation  to  all 
cell  functions,  which  are  as  one,  properly  balanced. 

Now  it  appears  reasonable  to  assume  that,  if  during  senescence 
and  slow  degenerations  a  loss  of  those  chromosomes  occurs  which 
are  concerned  with  the  exercise  of  specific,  higher  and  more  re- 
cently acquired  functions,  cell  balance  is  necessarily  upset.  For 
only  the  more  persistent,  ontogenetically  older  chromosomes  re- 
main. They,  therefore,  either  predominate  or  entirely  control 
future  cell  life.  Thus  races  of  cells  develop  which  stand,  either  still 
near  to  the  normal,  or,  far  away,  quite  abnormal. 

In  either  instance,  cells  deviate  more  or  less  completely  from 
their  ancestors.  They  are  strong  in  vegetative,  weak  or  perverse  in 
their  functional  attributes.  They  are  tumor  cells  of  higher  or  lower 
differentiation. 

It  must  be  at  present  left  undecided  whether  in  addition  to  this 
essential  loss  of  higher  chromosomes  certain  stimuli  are  required 
to  set  this  new  cell  mechanism  in  motion.  It  is  conceivable  that 
this  is  so,  just  as  the  spark  is  necessary  to  set  off  the  explosion. 
In  favor  of  it  is  the  origin  of  many  tumors  under  the  influence 
of  specific  types  of  chronic  infections  and  inflammations.  More- 
over, certain  teratoid,  embryonic,  undifferentiated  rests  (hamarto- 
mata,  choristomata)  may  remain  fixed  and  stationary.  But  here  we 
must  consider  that  as  yet  undifferentiated,  never  fully  completed 


294  GENERAL  PATHOLOGY 

cells  cannot  be  compared  to  those  in  which  regression  from  full 
development  is  accomplished  by  a  much  greater  upset  of  balance 
and  a  much  greater  revolution  in  cell  life.  Whether  or  not  an  addi- 
tional stimulus  is  required  to  set  the  remaining  latent  qualities  in 
motion,  the  real  cause  of  tumor  growth  lies  in  the  cell,  just  as  the 
cause  of  an  explosion  lies  in  the  explosive  substance.  The  tumor 
cell,  by  degenerative  loss  of  those  higher  attributes  which  originally 
gave  it  balance  and  differentiation,  is  without  restraining 
support,  continually  reproducing  itself,  never  again  to  reach  its 
former  self. 

EXPERIMENTAL   STUDY   OF   TUMORS 

In  recent  years,  since  about  1900,  the  experimental  study  and 
research  of  tumors,  more  especially  of  cancer,  have  occupied  much 
of  the  attention  of  investigators.  Two  main  lines  of  attack  have 
been  pursued,  first,  the  artificial  production  of  tumors,  secondly, 
the  biological  and  morphological  behavior  of  transplanted  animal 
tumors.  Neither  line  of  research  has  so  far  brought  us  much  nearer 
to  the  solution  of  the  etiology  of  and  cell  mechanism  in  tumor 
growths  although  they  have  demonstrated  some  interesting  facts 
about  cell  life. 

The  artificial  production  of  true  tumors  has  been  quite  unsuccess- 
ful, although  it  has  been  possible  to  obtain  by  certain  irritants  more 
or  less  extensive  proliferation  and  growth  of  one  or  the  other  cell 
type.  Thus,  Podwyssotzky  obtained  excessive  connective  tissue 
formations  by  local  administration  of  infusorial  silica  (from  sponges 
and  coats  of  diatomes,  so-called  "kiese!guhr").This  tissue  was  rich 
in  phagocytic  giant  cells.  This  growth  has  been  explained  as  due  to 
direct  mechanical  irritation  of  cells,  or  to  physico-chemical  stimula- 
tion by  iron  and  calcium  phosphates.  In  any  case,  this  is  in  no  way 
to  be  compared  to  the  manner  and  character  of  tumor  growth. 

Somewhat  closer  to  the  pictures  of  epithelial  tumors  are  the  re- 
sults obtained  by  Fischer,  Stoeber,  Wacker,  Florito  and  others  with 
injections  of  Scarlet  R  and  Sudan  III  (in  oily  solutions)  into 
skin,  urinary  bladder,  stomach,  breast  and  endothelium  of  lymph 
glands.  They  led  to  marked  hyperplasia  and  at  least  partial  infil- 
trating growth  of  epithelium  into  deeper  and  surrounding  tissue. 


CHANGES  IN  LOCAL  CELL  RELATIONS          295 

Stoeber  and  Wacker  also  obtained  a  considerable,  cancer-like,  epi- 
dermal growth  with  epidermal  pearls  by  injection  of  protein  de- 
composition products  (indol  and  skatol  in  oil).  But  these  growths 
remained  limited  to  the  immediate  locality  reached  by  the  irritant. 
The  cells  did  not  continue  independent  existence,  did  not  by  them- 
selves progressively  infiltrate  and  did  not  metastasize,  although 
they  were  in  some  cases  dislocated  and  even  reached  neighboring 
lymph  glands  with  the  lymph  stream.  But  the  power  of  growth 
was  soon  exhausted  and  metastasis  with  replacement  of  the  phys- 
iological tissue  by  these  cells  has  never  been  observed.  The  same  is 
true  in  regard  to  the  recent  experimental  work  of  Yamagiwa,  and 
Ichikawa,  who  with  coal  tar  produced  cancer-like  growths  with 
misplacement  of  cells  into  neighboring  lymph  glands  (see  under 
Metastases).  Common  to  all  irritants  leading  to  cell  proliferation  is 
their  ability  to  dissolve  lipoids  (see  under  Progressive  Cell  changes) . 
Moreover,  the  cell  proliferation  is  here  a  direct  response  to  the 
irritant  and  does  not  maintain  itself  without  its  continued  stimulating 
effect. 

These  artificial  growths  may,  therefore,  be  compared  to  those 
interesting  and  sometimes  extensive  hyperplasias  of  epithelial 
cells  which  are  occasionally  associated  with  long-continued  granu- 
lomatous  inflammations  of  skin,  lips,  tongue,  and  elsewhere, 
especially  in  syphilis  and  tuberculosis.  It  is  well  known  that  such 
abnormal  hyperplasias  easily  cross  the  line  to  tumors  (cancers)  but 
in  themselves  lack  the  essential  neoplastic  character  of  independ- 
ent, progressive  growth  and  ability  of  cells  to  overcome  physiolo- 
gical opposition  beyond  the  inflamed,  irritated  focus. 

Something  else  is  still  required  or  lacking  in  these  cells  to  stamp 
them  as  tumor  cells. 

Very  productive  has  been  the  field  of  experimental  investigation 
into  the  problems  of  tumor  growth  in  animals  during  the  last 
twenty  years,  since  it  has  been  found,  contrary  to  older  views, 
that  mature,  benign  and  immature,  malignant  neoplasms  are 
common  in  mammals,  birds  and  even  among  cold-blooded  ani- 
mals. The  mouse  has  for  frequency  of  its  tumors  become  particu- 
larly famous  as  an  animal  for  cancer  research,  especially  since  Jensen 
reported  that  he  had  been  able  to  propagate  by  transplantation  a 


296  GENERAL  PATHOLOGY 

mammary  tumor  of  the  mouse  for  two  and  one-half  years  through 
nineteen  generations.  This  opened  a  wide  field  for  the  study  of  the 
conditions  under  which  these  tumors  grow  and  their  general  bio- 
logical behavior  towards  a  host,  but  it  does  not,  of  course,  disclose 
anything  about  the  origin  of  tumors. 

Transplantation  of  tumor  tissue  from  one  animal  to  another, 
follows  the  general  laws  of  transplantation  previously  considered. 
In  man  only  autotransplantation  succeeds,  not  isotransplantation 
or  heterotransplantation,  i.e.,  from  man  into  animals.  Even  in 
animals  heterotransplantation  does  not  succeed  (tumor  of  one 
species  into  another).  Then  also,  benign,  fully  matured  tumors 
are  capable  only  of  autotransplantation,  and  isotransplantation 
fails,  while  malignant,  dedifferentiated  tumor  cells  are  capable  of 
growth  in  the  tissues  of  a  host  of  the  same  species,  but  in  no  other. 
Most  frequent  of  these  are,  as  already  said,  mouse  cancers,  then 
mouse  sarcomata  or  mixed  growths.  Rats  show  similar  tumors, 
dogs  sarcomata,  and  fowls  sarcomata.  Some  of  these  sarcomata  are 
of  doubtful  character  and  are  possibly  infective  granulomata. 

In  transplantation  into  an  animal  of  the  same  species  the  graft 
is  introduced  subcutaneously  under  sterile  conditions  or  as  an  emul- 
sion. Small  intact  fragments  seem  to  give  better  results.  If  the 
transplantation  is  successful,  a  tumor  develops  at  the  point  of  inoc- 
ulation in  from  one  to  two  weeks.  It  grows  and  behaves  like  the 
original  and  may  be  utilized  for  further  transplants.  The  cells  in 
the  new  growth  are  derived  from  the  introduced  tumor  cells,  the 
stroma  from  the  tissue  of  the  host.  The  original  stroma  of  the 
tumor  disintegrates.  Even  malignant  tumors  do  not  always  "take" 
or  may  grow  indifferently  in  another  animal  of  the  same  species, 
more  especially  when  derived  from  an  animal  of  distant  locality. 
A  cancer  from  a  German  mouse  may  not  grow  so  readily  in  an 
English  mouse  although  its  growth  is  abundant  in  another  German 
mouse.  Succeeding  passages  through  other  English  mice  may  im- 
prove its  power  to  grow  in  them.  The  "take"  of  the  graft  seems  to 
depend  upon  the  formation  and  maintenance  of  a  vascularized 
stroma  from  the  host,  that  is,  upon  the  reaction  of  the  host  to  the 
introduced  tumor  cells.  Where  this  is  lacking  the  cells  become 
necrotic  and  are  resorbed. 


CHANGES  IN  LOCAL  CELL  RELATIONS         297 

An  important  and  interesting,  but  not  quite  clear  phenomenon 
is  the  resistance  of  certain  animals  of  the  same  species  to  tumor 
grafts. 

Older  animals  seem  to  show  more  of  this  than  young  ones. 
Again,  in  some  animals  the  tumor,  after  a  primary  take,  may  dis- 
appear, be  resorbed,  and  such  animals  are  then  more  resistant  to 
subsequent  inoculations.  This  has  been  termed  tumor  immunity, 
which  is  misleading  in  name.  For  it  appears  that  this  refractoriness 
is  of  a  different  character  than  bacterial  or  infectious  immunity. 
Dead  tumor  cells  are  incapable  of  inducing  this  immunity.  More- 
over, the  immunity  is  not  specific  and  may  be  brought  about 
by  inoculation  with  normal  tissues,  defibrinated  blood  but  not  the 
serum.  But  here,  also,  the  phenomenon  is  distinctly  racial.  Mouse 
can  be  immunized  only  with  mouse  tissue,  rat  with  rat  tissue. 
The  immunity  reaches  its  height  and  limit  in  about  ten  days  and 
then  declines. 

Interesting  is,  further,  the  fact  that  this  sort  of  immunization  is 
only  prophylactic;  it  exerts  no  influence  on  an  already  existing  and 
growing  tumor.  The  immunizing  capability  does  not  reside  in  the 
blood,  and  attempts  to  confer  passive  immunity  by  it  have  failed. 
Ehrlich  attributed  these  unique  phenomena  to  what  he  termed 
the  principle  of  athrepsia  (0p^ns  —  nutrition).  He  assumes  two 
types  of  nutritive  materials,  ordinary  and  specific.  When  the 
last  is  absent  the  tumor  does  not  "take,"  or  a  tumor  attracts  and 
consumes  all  of  it;  subsequent  inoculation  will  then  fail  and  metas- 
tases  cannot  form.  According  to  Ehrlich,  the  question  of  tumor 
growth  comes  down  to  a  struggle  between  body  and  tumor  cells 
for  specific  foodstuff.  Thus  growth  and  generalization  of  tumor 
cells  depend  upon  their  avidity.  These  views  are  not  shared  by 
Bashford,  Murray  and  Haarland,  who  see  the  cause  of  this  im- 
munization in  an  actively  acquired  disturbance  in  relation  between 
cancer  cells  and  stroma  whereby  the  latter  remains  insufficient  or 
does  not  react  at  all,  and  thus  the  tumor  cells  die  and  are  resorbed. 


CHAPTER  IV 

PATHOLOGICAL  CHANGES  IN  GENERAL  CELL,  TISSUE 
AND  ORGAN  INTERRELATIONS 

I.    DISTURBANCES    OF  BLOOD  AND   LYMPH    CIRCULATION 

THE  disturbances  of  blood  and  lymph  circulation  concern  us 
here  only  in  their  general  characters  and  bearings. 

i .  PATHOLOGICAL  CHANGES  IN  THE  AMOUNT  AND  QUALITY  OF  THE 
BLOOD.  Blood,  a  fluid  tissue,  consists  of  plasma  (water,  colloids, 
salts)  in  which  corpuscles  or  cells  are  suspended.  The  blood  pres- 
sure depends  upon  the  quantity  of  blood  and  the  tone  of  the  vessels 
and  is  a  necessary  corollary  of  blood  flow.  According  to  the  recent 
researches  of  Plesch,  the  quantity  of  blood  amounts  to  about 
one-nineteenth  of  the  body  weight  or  5.23  per  cent,  (about  4 
liters  of  blood  in  man  (Bayliss).  It  circulates  in  55  seconds  in  65 
pulse  beats  and  the  quantity  which  is  discharged  by  the  heart 
during  systole  varies  between  59  and  240  c.c.  The  volume  of 
blood  which  circulates  in  a  minute  in  an  average  body  weight 
of  70  kilos  is  from  4000  to  4300  c.c.  and  may  be  raised  over  ten 
times.  Even  under  physiological  conditions  the  circulation  is, 
therefore,  open  to  considerable  variations. 

The  way  in  which  the  blood  circulates  was  first  clearly  demon- 
strated in  1616  by  Harvey  (Leonardo  da  Vinci,  a  century  before 
Harvey,  had  come  very  close  to  it).  He  saw  the  blood  sent  from 
the  heart  into  the  arteries  and  returned  to  the  heart  by  the  veins. 
Capillary  circulation  was  not  demonstrated  until  van  Leeuwen- 
hoek's  invention  of  the  microscope  enabled  him  to  see  this  in  the 
tail  of  the  tadpole  in  1686. 

A  pathological  increase  in  the  whole  amount  of  blood  is  known 
as  plethora  vera.  Until  some  time  ago  the  occurrence  of  a  real 
plethora  was  doubtful  because  experimentally  it  has  been  found 
impossible  to  produce  it.  Nevertheless  this  pathological  occurrence 

298 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    299 

is  now  assured.  It  goes  along  with  hyperplasia  of  blood-forming 
organs  (bone  marrow,  spleen)  and  an  absolute  increase  in  the 
number  of  circulating  cells.  Red  blood  corpuscles  rise  to  8,000,000 
and  over.  The  disease  known  as  polycythemia  rubra  (Vaquez* 
disease)  is  of  this  nature.  It  is  not  settled  whether  it  is  the  result  of 
lessened  blood  destruction  or  an  increased  blood  formation.  In 
some  instances,  as  in  the  polycythemia  occuring  in  high  altitudes, 
it  results  from  direct  stimulating  effects  on  blood-forming  organs. 

By  plethora  serosa  is  understood  an  increase  of  blood  fluid  only, 
without  corresponding  increase  in  blood  cells.  It  results  from  failure 
in  the  regulatory  mechanism  between  blood  and  lymph  system 
on  account  of  toxic  influences  (chronic  nephritis,  etc.;  see  Edema). 
Plethora  serosa  is  to  be  distinguished  from  hydremia  in  which 
only  a  relative  increase  in  fluid  occurs.  It  follows  upon  large  hemor- 
rhages (where  the  fluid  part  of  the  blood  is  more  quickly  restored), 
also  intoxications  or  infections  which  destroy  large  numbers  of 
blood  cells.  A  diminution  in  the  amount  of  blood  is  known  as  ane- 
mia or  oligemia.  It  follows  either  mechanical  (hemorrhage)  or 
destructive  (toxic)  loss  of  blood.  Rapid  withdrawal  of  M  kg.  may 
lead  to  loss  of  consciousness,  of  K  to  2  kg.  to  death.  Animals  may 
lose  as  much  as  two-thirds  of  their  blood  volume.  Death  results 
here  from  lowering  of  blood  pressure  and  insufficient  friction  with 
the  vessel  wall. 

In  the  chronic,  slowly  progressing  anemias  the  amount  of  blood 
sinks  gradually,  especially  in  its  cellular  elements.  They  produce, 
therefore,  no  mechanical  circulatory  disturbance. 

Anhydremia,  loss  of  water  from  the  blood,  results  from  rapid 
withdrawal  of  fluids  from  the  blood  in  severe  diarrhea,  dysentery, 
cholera,  etc.  Here  the  blood  concentrates,  becomes  thicker,  darker, 
tarry  and  the  red  cell  count  rises  to  6K  million.  The  result  is  in- 
creased viscosity  (internal  friction)  of  the  blood  and,  therefore, 
greater  difficulty  in  circulation.  The  blood  viscosity  is  also  increased 
by  an  excess  of  CO2,  but  diminished  by  O.  The  relation  of  salts 
to  the  colloidal  contents  and  the  influence  of  salt  contents  on 
the  proteids  of  the  blood  have  undoubtedly  an  influence  on  the 
mechanism  of  the  general  circulation,  but  just  how  is  yet  to  be 
determined. 


300  GENERAL  PATHOLOGY 

2.  LOCAL  CHANGES  IN  BLOOD  CIRCULATION.  We  can  dis- 
tinguish: (a)  An  increased  flow  to  parts  (active,  arterial  hyperemia) 
or,  (6)  lessened  outflow  (passive,  venous  hyperemia). 

(a)  Active,  arterial  hyperemia  occurs  through  the  nervous 
system;  vasodilation  (paralytic,  or  irritative),  mechanical,  or  reflex, 
or  myogenic,  through  muscle  action,  finally  toxic  and  inflammatory. 

(6)  Passive,  venous  hyperemia,  results  from  interference  with 
the  flow  of  the  blood  stream,  by,  first,  increased  resistance  to  venous 
outflow  (mechanical  pressure  obstruction) ;  second,  lessened  active 
arterial  pressure  and  increased  venous  pressure  from  general  cir- 
culatory weakness  (heart  diseases) ;  third,  diminution  in  suction  of 
thorax  (heart  diseases  or  abnormal  contents  in  pericardium  and 
pleurae;  diaphragm  low). 

These  causes  lead,  by  increased  venous  and  capillary  pressure, 
to  gradual  backward  dilation  of  these  vessels  against  a  weakened 
arterial  pressure.  Unless  relieved,  they  are  followed  by  atrophy 
(from  pressure  and  nutritive  interference);  later  by  more  serious 
degenerative  lesions  (fatty  changes,  pigmentation),  finally  occur 
necrosis  and  waste  of  tissues  (cytolytic,  edematous  necrosis  of 
cells). 

(c)  Anemia.  Types:  (i)  Neurotic  anemia  from  cold  (vaso- 
constriction)  or  from  spastic  contraction  of  musculature.  (2)  Com- 
pression (mechanical)  anemia  by  pressure  from  outside.  (3)  Ob- 
struction anemia  by  interference  with  the  blood  stream  as  in  direct 
obliteration  of  vessels  without  or  with  insufficient  collateral 
circulation  (thrombosis,  embolism,  see  below).  The  results  may  be 
only  temporary  blanching,  provided  normal  or  collateral  circula- 
tion can  be  speedily  established.  But  when  this  is  impossible,  as 
for  example  in  obstruction  of  an  end  artery,  when  even  capillary 
anastomoses  fail,  necrosis  necessarily  follows  (see  under  Infarct 
below). 

If  collateral  circulation  can  be  established  and  maintained  suffi- 
ciently to  keep  up  circulation  in  a  tissue  deprived  of  its  physio- 
logical blood  supply,  the  collaterals  enlarge  and  even  the  small 
branches  thicken  and  may  assume  dimensions  of  main  arteries.  A 
beautiful  illustration  of  this  phenomenon  is  seen  in  congenital 
stenosis  of  the  aorta,  when  the  whole  amount  of  blood  may  be 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    301 

taken  care  of  by  enormously  enlarged  collateral  blood  vessels.  We 
have  here  a  fine  example  of  functional  adaptation  which  develops 
strictly  according  to  the  histomechanical  laws  of  Thoma — i.  e., 
increase  in  the  vessel  lumen  (the  diameter)  and  in  the  vessel  length 
depend  upon  the  rapidity  of  the  stream,  and  the  thickness  of  the 
wall  upon  the  tension  exerted  upon  it.  Consequently,  collaterals 
not  only  enlarge,  become  thicker  and  wider,  but  also  longer 
and  tortuous. 

3.  THROMBOSIS  (epopfios  =  clot).  A  thrombus  is  a  clot  arising 
within  a  vessel  during  life.  The  constituents  of  a  thrombus  are,  in 
the  vast  majority  of  instances,  derived  from  the  blood.  Not  all 
thrombi  are  of  uniform  origin  and  composition  and  the  mechanism 
of  their  development  is  not  identical  in  every  instance. 

Blood,  as  it  circulates  through  heart  and  blood  vessels,  is  nor- 
mally kept  fluid,  and  this  fluid  condition  remains  for  a  long  time 
even  when  a  vein  full  of  blood  is  ligatured  at  two  ends  and  removed 
from  the  body.  This  was  discovered  in  early  and  fundamental 
studies  on  blood  coagulation  by  Hewson,  Lister  and  Fredericq,  and 
confirmed  by  Briicke.  If  such  blood  is  stirred  with  a  glass  rod  it 
will  adhere  to,  and  jell  around,  the  rod.  Freund,  and  later  Hay- 
craft  and  Carlier  found  that  blood  remains  fluid  when  collected 
under  oil,  through  a  greased  cannula  or  in  a  vessel  greased  with 
vaseline  and  that,  if  beaten  with  a  rod  previously  oiled,  it  does  not 
coagulate.  If,  on  the  other  hand,  the  blood  is  poured  into  an  ordi- 
nary glass  vessel,  or  upon  a  slide,  it  will  clot  immediately.  In 
other  words,  contact  of  blood  with  a  foreign  body  that  it  can  wet 
and  adhere  to  starts  coagulation.  It  is  this  adhesion  between  the 
blood  and  a  foreign  substance  that  gives  the  conditions  which  are 
required  for  coagulation  and  such  conditions  may  arise  in  life 
by  disease  of  the  intima  of  blood  vessels  (injury  to  the  lining 
endothelium). 

We  know,  through  the  fundamental  observations  of  Buchanan, 
Alexander  Schmidt,  Hammarsten  and  others,  that  clotting  is  the 
result  of  action  of  a  substance  (thrombin)  upon  the  fluid  fibrino- 
gen  of  the  blood  which,  in  the  presence  of  Ca  salts,  precipitates  it 
to  solid  fibrin.  Both  are,  therefore,  blood  constituents,  but  inas- 
much as  the  blood  does  not  normally  coagulate  in  blood  vessels 


302  GENERAL  PATHOLOGY 

or  when  received  into  oily  surroundings,  it  follows  that  the  coagu- 
lating thrombin  must  be  derived  from  a  precursor  in  the  blood, 
and  this  is  spoken  of  as  prothrombin  or  thrombogen  (latent  throm- 
bin). The  question  then  arises,  what  is  prothrombin  and  what  ac- 
counts for  its  translation  into  active  thrombin?  Here  the  histolog- 
ical  and  experimental  investigations  of  Moravitz,  Eberth  and 
Schimmelbusch  and  Tait  have  brought  much  light,  because  they 
established  the  direct  relation  of  a  normal  blood  corpuscle,  the 
blood  platelet,  to  coagulation.  Blood  platelets,  originally  described 
by  Hayem  and  identified  by  Bizzozero,  are  now  recognized  as 
regular  organized  cellular  blood  constituents  and  correspond 
to  spindle-shaped  cells  in  the  blood  of  lower  animals.  Moreover, 
their  role  in  blood  coagulation  is,  according  to  the  latest  researches 
of  Tait,  identical  with  that  of  these  spindle  cells  in  lower  animals. 
Moravitz  showed,  and  in  this  he  was  confirmed  by  Bayne- Jones 
in  Howells*  laboratory,  that  blood  platelets  yield  on  solution  in 
water  a  substance  which,  in  the  presence  of  Ca  salts,  coagulates, 
that  is,  furnishes  thrombin.  Before  him  Eberth  and  Schimmelbusch 
had  already  pointed  out  that  adhesion  and  agglutination  of  blood 
platelets  to  an  injured  intima  are  an  important  primary  requisite 
of  thrombosis,  and  they  were  inclined  to  regard  platelets  as  the 
essential  component  of  thrombi.  Subsequent  histological  examina- 
tions fixed  the  role  of  the  platelets  as  the  prothrombin,  that  is, 
the  blood  elements  from  which  the  active  thrombin  is  derived. 
Blood  platelets  adhere  to  foreign  matter  (glass)  as  they  will  to  a 
pathologically  altered  intima.  By  cytolysis  (Tait)  they  then  yield 
thrombin,  which  precipitates  fibrin  around  themselves  and  other 
blood  elements.  Consequently  typical  thrombi  exhibit  a  stratified, 
laminated  appearance.  They  possess  a  scaffold  consisting  of  bars 
of  platelets  to  which  are  often  attached  a  fringe  of  leucocytes.  As 
blood  platelets  cytolyze,  fibrin  is  progressively  precipitated  in  fine 
interwoven,  increasing  threads  around  and  between  these  bars  and 
connects  them  by  a  thickening  network.  In  it  red  cells  are  arrested. 
Thus  a  very  characteristic  arrangement  of  platelets  and  cell  is 
produced  which  has  been  compared  to  the  arrangement  of  sand  at 
the  bottom  of  a  river,  which  is  thrown  into  ridges  and  depressions 
by  the  stream  (Aschoff).  Others  attribute  it  to  irregularities  in  the 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    303 

blood  current  establishing  eddies  and  relatively  quiet  areas  in 
which  adhesion  and  precipitation  may  more  readily  take  place,  or, 
still  others,  to  contractions  of  the  vessel  wall  (Ribbert).1 

But  these  changes  in  the  lining  endothelium  of  vessels  are  not 
alone  concerned  in  thrombus  formation.  Very  important  are  patho- 
logical changes  in  the  blood  composition  which  increase  the  tend- 
ency to  adhesion  of  its  formed  elements  and  also  to  coagulation. 
These  are  given  by  the  presence  of  bacteria  and  of  foreign  proteins 
in  the  blood,  bacterial  or  other  toxines  and  albuminous  material  from 
resorption  of  extensive  inflammatory  exudates  or  from  destroyed 
tissues,  burns,  etc.  In  pneumonia,  for  example,  as  much  as  2 
liters  of  softened  exudate  may  after  crisis  be  rapidly  thrown  into 
the  circulation.  Under  such  conditions  the  tendency  to  adhesion 
of  platelets  and  to  precipitation  is  very  great.  Very  slight  in- 
timal  injury  may  then  be  sufficient  to  lead  to  adhesion  of  throm- 
bocytes,  their  cytolysis  (thrombin  formation)  and  subsequent 
coagulation. 

In  a  number  of  these,  so-called  septic  thrombi  (that  is,  those 
which  occur  in  the  course  of  an  infection)  I  have  been  unable  to  dem- 
onstrate any  morphological  changes  in  the  intima,  and  while  the 
typical,  simple  thrombi  are  generally  very  firmly  attached  to  the 
vessel  wall,  the  septic  thrombi  are  often,  especially  in  very  large 
vessels,  like  the  main  pulmonary  artery,  rather  loosely  adherent. 
Moreover,  some  of  these  are  embolic  in  origin  (see  below). 

Finally  a  third  factor  is  of  importance  in  the  formation  of  thrombi, 
namely,  general  or  local  slowing  of  the  blood  current.  By  itself  it 
cannot  produce  thrombosis,  but  it  is  an  accessory  to  the  other  two, 
for  it  favors  adhesion  of  formed  elements  and  allows  fibrin  to 
accumulate.  Consequently,  thrombi  are  most  apt  to  form  in  circum- 
scribed vessel  dilatations  (aneurysms),  recesses  of  the  heart  and  in 
veins  where  circulation  is  even  normally  less  swift  than  in  arteries. 

1  It  seems  that  blunt  traumatic  injury  to  vessel  walls  is  occasionally  sufficient 
to  cause  thrombosis.  This  has  been  observed  in  thrombi  of  coronary  arteries 
of  the  heart  after  sudden  severe  trauma  over  the  pericordial  area — concussion 
in  prize  fighters  and  even  general  severe  muscular  exercise  as  in  a  case  reported 
by  Kaufmann.  My  colleague  Dr.  D.  D.  MacTaggart,  professor  of  medical 
jurisprudence  at  McGill,  observed  it  in  a  man  with  otherwise  intact  arteries 
who  was  thrown  off  a  trolley  car  and  violently  hit  the  ground  on  his^chest. 


304  GENERAL  PATHOLOGY 

Still  different  are  the  so-called  hyaline  thrombi  which  are 
frequent  in  small  vessels  and  capillaries  in  various  infections  and 
intoxications  (bacterial  toxines  and  poisons,  such  as  ricine).  They 
appear  homogeneous,  hyaline  and  consist  largely  and,  as  some 
think,  entirely  of  agglutinated  and  hemolysed  red  blood  cells. 
Some  claim  that  under  high  magnification  they  also  exhibit  fine 
fibrin  threads.  This  is  doubtful.  White,  so-called,  chicken  fat 
thrombi  are  made  up  of  platelets,  leucocytes  and  much  fibrin 
(terminal,  agonal  clots).  They  are  evidences  of  slow  coagulation, 
occur  often  in  slow  death  with  prolonged  agony  and  generally  are 
found  around  and  between  the  heart  muscle  trabeculae  and  in  large 
arteries.  Their  origin  has  been  attributed  to  a  gradual  slow  ebbing 
of  the  circulation  when  the  axial  stream,  carrying  erythro- 
cytes  is  still  relatively  strong,  while  at  the  periphery  stagna- 
tion becomes  pronounced.  Thus  large  numbers  of  platelets  and 
wandering  leucocytes  gradually  accumulate,  attach  themselves 
to  the  wall  and  to  each  other  and  much  fibrin  is  precipitated 
loosely  around  them  without  incorporating  red  blood  cells.  Others 
deny  this  and  see  in  them  only  a  slow  post-mortem  coagula- 
tion similar  to  the  formation  of  the  buffy  coat.  These  clots 
are  gelatinous,  moist,  tenacious,  and  adhere  like  glue  to  the 
surface.  They  are  relatively  elastic  and  tear  readily.  Finally 
red  thrombi  (as  compared  to  the  typical,  stratified  variety)  occur 
in  massive  blood  destruction  with  rapid  coagulation.  They  also 
make  up  a  number  of  marantic  (papal  vtiv  —  to  waste)  thrombi 
occurring  especially  in  end  arteries  (lungs,  etc.)  shortly  before 
death  in  emaciated  individuals.  They  are  looser  than  the  mixed 
variety  and  contain  a  very  large  number  of  red  cells. 

Contrasted  with  these  ante-mortem  thrombi  stand  post-mortem 
coagula  or  cruor.  They  are  dark  red,  gelatinous,  more  or  less  elastic, 
moist  and  crumbling,  never  with  any  structural  arrangement.  They 
lie  unattached  in  vessels  and  cavities  and  consist  simply  of  loose 
mixtures  of  red  blood  cells,  leucocytes  and  fibrin.  Thrombi  of 
primary  origin  are  spoken  of  as  autochthonus  (avros  =  self, 
xO&v  —  land).  Others  are  secondary,  engrafted  upon  some  other 
obstructing  agent  (see  under  Embolus,  below).  From  their  original 
seat  they  may  extend  long  distances,  sometimes  obstructing  the 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS  305 

whole  length  of  a  vessel  (mostly  in  veins,  for  example,  extension 
from  veins  of  a  leg  into  vena  cava  inferior  and  even  into  the  heart) . 

Results  of  Thrombosis,  (i)  Simple  shrinking,  drying  and  calci- 
fication. Parts  of  calcified  thrombi  are  occasionally  dislocated  and 
circulate,  especially  in  large  veins,  as  phleboliths.  (2)  Simple  soften- 
ing (autolysis  of  thrombi).  Here  is  great  danger  of  dislocation  and 
embolism.  (3)  Septic,  bacterial  softening.  This  may  exist  from  the 
start  (septic  thrombus)  or  occur  subsequently.  Danger  of  septic 
emboli.  (4)  Organization,  replacement  of  thrombus  by  granulation 
tissue.  From  the  vessel  wall  fibroplasts  grow  with  endothelial  buds 
into  the  thrombus.  Its  cell  elements  disintegrate  and  are  phago- 
cyted.  Ultimately  fibrous  tissue  takes  the  place  of  the  thrombus. 
If  it  is  attached  only  to  one  side  of  the  vessel  wall,  retraction  fol- 
lows and  circulation  is  thus  once  more  established.  In  completely 
obstructing  thrombi  the  granulation  tissue  remains  canalized  by 
newly  formed  blood  vessels  and  thus  circulation  is  reestablished 
through  the  permanent  scar  tissue  with  enlargement  of  the  vessel 
and  thickening  of  the  wall.  This  occurs  from  hyperplasia  of  mus- 
culature and  adventitia. 

4.  EMBOLISM  (evfiaXXeiv  =  to  throw  into).  By  an  embolus  we 
understand  a  solid,  movable  body  within  the  circulation,  which,  in 
the  majority  of  instances,  is  finally  arrested  in,  and  blocks  a  vessel. 
The  most  common  emboli  are  thrombotic  in  origin.  Either  a  whole 
or  part  of  a  thrombus  becomes  dislodged  and  is  rearrested  at  a 
distant  point  where  the  caliber  of  a  vessel  is  too  narrow  to  allow 
further  passage.  Emboli  are  of  great  importance  because  blockage 
of  a  larger  vessel  may  lead  to  serious  consequences,  infarctions 
and  even  death.  Emboli  follow  generally  the  course  of  the  blood. 
Thus,  emboli  entering  the  venous  circulation  are  carried  to  the 
right  side  of  the  heart  and  are  arrested  in  the  pulmonary  circula- 
tion. Depending  upon  the  size  of  the  emboli,  even  larger  pulmon- 
ary branches  and  the  conus  arteriosus  may  be  blocked.  Then 
follows  thrombosis  before  and  after,  so  that  blood  casts  as  far 
back  as  the  right  ventricle  may  form. 

Emboli  from  the  left  side  of  the  heart  (from  inflammatory 
deposits  on  heart  valves)  are  led  into  the  arterial  circulation,  where 
they  are  arrested  in  end  arteries  (cerebral  arteries,  arteria  fossae 

Sylvii,  lenticulostriate,  in  spleen,  kidney,  mesentery)  and  others. 
20 


306  GENERAL  PATHOLOGY 

The  curious,  so-called,  paradox  embolism  occurs  through  a 
patent,  wide  foramen  ovale  which  allows  an  original  venous  embo- 
lus  to  enter  the  arterial  system.  Occasionally  the  embolus  may 
thus  be  arrested  in  the  auricular  septum. 

Very  unusual  are  so-called  retrograde  emboli.  They  occur  in  the 
venous  system,  probably  through  reflux  of  venous  waves  in  chronic 
venous  congestion  (strong  venous  and  weak  arterial  pressure), 
aided  by  increased  positive  thoracic  pressure  through  forced  res- 
pirations (cough,  dyspnea,  etc.)  (Ribbert).  Under  such  conditions 
emboli  may  be  forced  from  the  vena  cava  into  renal  or  liver  veins. 

It  has  already  been  stated  that  just  as  soon  as  the  embolus  is 
arrested  it  is  gradually  enveloped  by  a  locally  forming  thrombus 
(secondary  thrombus).  The  seat  of  predilection  for  settlement  of 
emboli  is  at  the  bifurcation,  forking,  of  vessels  (kidney  emboli). 

The  results  of  emboli  depend,  of  course,  entirely  on  the  impor- 
tance of  the  obstructed  vessel.  Obstruction  of  large  branches  of  the 
coronary  heart  circulation  or  of  the  pulmonary  circulation  leads 
generally  to  rapid  death  (cessation  of  circulation).  Very  rarely 
strong  individuals  survive  in  this  condition  through  collateral  circu- 
lation. In  the  pulmonary  circulation  this  seems  occasionally  to  be 
maintained  through  the  bronchial  arteries  with  esophageal,  pericar- 
dial,  phrenic  and  mediastinal  anastomoses.  Results  in  obstruction  of 
smaller  vessels  depend  entirely  on  the  collateral  circulation.  If  a 
strong  collateral  circulation  can  be  maintained,  no  bad  results 
may  follow,  however,  in  anatomical  or  even  functional  end  arteries 
such  as  exist  in  brain,  heart,  kidney  and  spleen,  it  leads  to  infarction. 

By  infarction  is  meant  necrosis  and  sequestration  of  tissues  as  a 
result  of  complete  cessation  of  circulation  in  a  district,  consequent 
on  thrombotic  or  embolic  obstruction  of  end  arteries  or  under  con- 
ditions which  do  not  allow  collateral  circulation  of  sufficient  force 
to  nourish  the  involved  parts  (weak  general  circulation).  Infarcts 
are  either  simple,  anemic,  or  hemorrhagic  when  massive  hemor- 
rhagic  extravasation  and  infiltration  occur  within  the  sequestrated 
tissue  (hence  the  name,  from  infarcire  =  to  stuff,  although  this 
phenomenon  is  really  secondary  and  not  the  essential  lesion). 
The  size  and  shape  of  the  infarct  vary,  of  course,  to  correspond  to 
the  area  supplied  by  the  obstructed  branch.  Most  frequently  they 
are  wedge-shaped  with  the  apex  towards  the  hilus  of  an  organ  (seat 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    307 

of  embolus),  the  base  towards  the  surface.  But  they  may  be 
irregular  and  ragged,  multiple,  and  even  confluent. 

The  development  of  infarcts  has  been  the  field  for  a  good  deal 
of  experimental  study  and  is  not  yet  in  all  points  quite  clear.  Re- 
cent investigations  by  Karsner  and  Austin  have  added  much 
valuable  information  to  the  older  knowledge.  Based  on  the  work  of 
Beckman,  Weigert  and  Thoma  it  has  been  generally  held  that  when- 
ever a  branch  of  an  end  artery  is  suddenly  obstructed,  the  part 
becomes  immediately  blanched  and  anemic,  while  the  edges  show 
compensatory  hyperemia  from  capillary  engorgement  which  is  not 
strong  enough  to  force  blood  into  the  anemic  district. 

The  investigations  of  Karsner  and  Austin,  however,  have  demon- 
strated that,  regardless  of  all  circulatory  conditions,  all  infarcts 
of  the  kidney  and  spleen  of  the  dog  are  at  first  hyperemic,  then 
hemorrhagic  and  finally  become  pale  from  coagulation  necrosis. 
They  conclude  that  the  hyperemia  is  due,  and  proportional,  to 
the  vascular  pressure  within  an  organ  as  a  whole,  and  not  due  to 
reflux  of  blood  from  veins. 

Necrosis  of  the  infarcted  area  progresses  more  rapidly  in  infarcts 
in  those  organs  in  which  the  circulation  is  weakened  (high  venous, 
low  arterial  pressure)  than  in  organs  with  normal  circulation. 
Within  two  hours  after  infarction  blood  corpuscles  conglutinate 
(clump  and  fuse).  This  reaches  its  height  in  24  to  48  hours.  After 
48  hours  hemoglobin  dissolves  and  the  corpuscles  fade.  The  hemo- 
globin is  washed  away  from  center  to  periphery  by  plasmatic 
currents.  The  pallor  of  anemic  infarcts  is  therefore  due  to  decolori- 
zation  of  conglutinated  and  coagulated  blood.  Degeneration  and 
necrotic  changes  in  the  parenchyma  put  in  an  early  appearance.  At 
the  end  of  48  hours  necrosis  is  complete.  The  connective  tissue  dis- 
integrates less  rapidly,  occasionally  a  good  deal  later.  Thus,  the 
whole  sequester  becomes  necrotic  and  autolyzes,  unless  the  embolus 
or  thrombus  is  infected,  in  which  case  septic,  bacterial  softening  and 
infection  follow. 

Some  infarcts,  especially  in  organs  with  double  circulation  (lung, 
liver)  but  also  in  the  spleen,  remain  deeply  hemorrhagic.  They  are 
observed  only  when  the  general  circulation  is  weak  and  venous 
pressure  is  much  increased,  while  the  arterial  pressure  is  lowered. 


308  GENERAL  PATHOLOGY 

Cohnheim  attributed  this  hemorrhagic  infarction  to  reflux  from  the 
veins  into  the  area  of  minus  arterial  pressure.  However,  anatomi- 
cal as  well  as  experimental  evidence  obtained  by  tying  the  veins 
has  not  substantiated  this  view.  It  is,  therefore,  assumed  that  the 
blood  is  essentially  the  arterial  blood  of  the  infarct  and  depends 
upon  the  arterial  pressure  of  the  surrounding  living  tissues.  The 
question  then  arises,  why  are  some  infarcts  later  pale  and  some 
deeply  hemorrhagic?  This  seems  to  depend  upon  the  degree  of 
hemorrhagic  infarction.  They  are  thus  hemorrhagic,  especially  in 
organs  with  double  circulation.  Here  the  second  circulation  is, 
with  strong,  normal  arterial  pressure,  able  to  compensate  for  the 
eliminated  first.  But  in  weak  circulation  (heart  disease),  with  low 
arterial,  and  strong  venous  pressure,  it  is  unable  to  establish  and 
maintain  collateral  circulation.  The  collateral  vessels  can  then 
only  pour  their  blood  into  the  infarcted  area,  superimpose  it,  so 
to  speak,  on  the  already  stagnant  blood  of  the  first  circulation  and 
thus  create  a  dense  blood  excess  which  massively  extra vasates.  In 
anemic  infarcts  extravasation  is  unimportant.  Similar  hemorrhagic 
infarctions  occur  at  times  during  the  increasing  decline  in  blood 
pressure  in  prolonged  agony  without  an  obstructing  embolus.  These 
agonal  infarcts  are,  therefore,  not  infrequent  in  the  lungs.  Infarcts 
in  the  liver  are  very  rare  and  occur  only  when  both  liver  circula- 
tions are  profoundly  interfered  with  (arterial  weakness  and  venous 
stasis  in  the  portal  system).  In  the  spleen  the  peculiar  mechanism 
of  the  circulation  with  free  blood  in  pulp  and  the  extensive  sys- 
tem of  anastomizing  sinuses  seems  also  favorable  to  formation  of 
hemorrhagic  infarcts. 

It  has  been  stated  that  infarcts  soften  rapidly.  When  the  infarct 
is  not  infected  and  does  not  give  rise  to  purulent  necrosis,  organi- 
zation of  the  defect  is  accomplished  by  growth  of  granulation  tissue 
from  the  edges.  At  the  expiration  of  one  week  this  connective  tissue 
growth  becomes  marked  and  the  infiltration  by  leucocytes  and 
hyperemia  of  the  edges  subside.  Organization  progresses  as  well  in 
organs  with  diminished  circulation  as  in  those  in  which  general 
circulation  is  normal.  Regeneration  of  parenchymatous  structures 
does  not  occur,  although  proliferative  changes  at  the  periphery 
of  the  infarct  are  visible. 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    309 

The  center  of  large  infarcts  remains  unorganized  and  simply 
collapses.  Next  to  thrombotic  emboli,  fat  emboli  are  the  most 
important.  They  owe  their  origin  to  entrance  of  neutral  fat  into 
the  circulation  (fractures,  concussions,  and  trauma  of  subcutaneous 
fat).  Fat  enters  the  veins  and  embolizes  in  the  lungs  (fat  casts). 
Some  of  it  may  pass  the  lungs  to  embolize  in  brain,  kidneys, 
glomeruli  and  heart. 

In  extensive  fat  embolism  death  results  from  interference  with 
the  pulmonary,  brain  or  heart  functions.  Experimentally  a  con- 
siderable amount  of  oil  is  found  necessary  to  kill  (2  c.c.  oil  per  i  kg. 
weight  of  animal).  When  the  animal  escapes  death  fat  is  gradually 
absorbed.  Even  extensive  fat  emboli  may  not  be  grossly  visible; 
fat  stains  will  disclose  their  presence  on  microscopic  examination. 
Gas  or  air  emboli  from  accidental  introduction  into  veins  (syringe) 
may  sometimes  cause  serious  consequences  in  the  coronary  system 
of  the  heart. 

Tumor  cell  emboli,  from  dislodged  cells  especially  in  malignant 
tumors,  are  frequent  and  have  been  considered  under  metastasis. 
Occasionally  parasitic  eggs  (tape  worms,  etc.)  and  bacterial  clumps 
embolize  smaller  vessels. 

5.  HEMORRHAGE.  Hemorrhage  is  discharge  of  whole  blood  from 
vessels.  Hemorrhages  are  divided:  (i)  According  to  extent  and 
form;  small,  punctuate — petechiae;  flat  streaky — ecchymoses,  sug- 
glations;  circumscribed,  cavitated — hematomata.  (2)  According  to 
their  source;  epistaxis — from  the  nose;  hematuria — from  urinary 
tract;  hematemesis — from  stomach  (blood  vomit);  hemoptysis 
from  respiratory  tract;  metrorrhagia — from  female  genitals,  etc. 
Hemorrhage  takes  place  with  rupture  of  vessel  wall,  per  rhexin  or 
with  intact  wall,  per  diapedesin.  Vessel  wall  rupture  results  from 
external  trauma  or  internal  pressure  effects,  usually  on  weakened 
arteries  (disease  of  arterial  walls,  aneurisms,  etc.).  Diapedesis  occurs 
in  venous  congestion,  in  inflammatory  stasis,  infections  and  septic 
or  toxic  injury  to  vessel  walls  (purpura,  general  sepsis,  scurvy, 
icterus,  hemorrhagic  diphtheria,  etc.). 

Nervous  influences  may  have  similar  results  (hysterical  stig- 
mata, vicarious  hemorrhages  from  mucous  membranes  in  amenor- 
rhea,  etc.).  Bleeding  ceases  when  the  vessel  is  closed  by  a  thrombus. 


3io  GENERAL  PATHOLOGY 

This  is  not  the  case  in  bleeders  (hemophilia),  but  whether  from  an 
abnormal  composition  of  blood  or  faulty  construction  of  vessels  is 
still  quite  uncertain. 

Hemorrhages  into  tissues  are  gradually  resorbed.  Watery  ele- 
ments disappear  and  blood  pigment  is  set  free  as  hemosiderin  and 
hematoidin  (see  under  Pigmentation).  In  large  destructive  hemor- 
rhages (especially  in  the  brain)  the  blood  elements  maybe  absorbed, 
but  clear  fluid  remains  (apoplectic  cysts).  In  other  cases  granula- 
tion tissue  covers  and  fills  the  defect. 

6.  SHOCK.  Shock  is  a  condition  which  very  closely  resembles 
the  results  of  severe  hemorrhage.  It  is  a  collective  name  under 
which  are  included  a  number  of  conditions  of  different  etiology  and 
mechanism.  Shock  may  be  an  affection  of  the  nervous  system  pure 
and  simple;  it  may  be  allied  to  hysteria  (shell  shock)  and  quite  dis- 
tinct from  wound  or  surgical  shock.  This  comes  on  some  time 
(hours)  after  a  wound  or  operation  and  shows  itself  by  pallor, 
coldness,  sweating,  vomiting,  low  blood  pressure  and  often  exten- 
sive thirst.  Here  occurs  a  collapse  of  the  whole  circulatory  mechan- 
ism, not  due  to  failure  of  the  heart  or  the  central  nervous  system, 
but  very  similar  to  what  occurs  in  severe  hemorrhage  from  loss  of 
blood  volume.  Evidence  indicates  that,  although  in  surgical  or 
wound  shock  no  blood  is  actually  removed  from  the  body,  it  is 
pooled  in  the  great  dilatations  of  the  circulatory  tube.  This  amount 
of  blood  is  therefore  lost  to  the  circulation  as  in  real  blood  loss. 

Recent  investigations  have  shown  that  the  occurrence  of  this 
shock  stands  in  relation  to  the  extent  of  tissue  injury  during  an 
operation  (C.  Wallace)  and  that,  as  shown  by  Cameron  and  Bay- 
liss,  it  is  probably  of  toxic  origin  (rapid  removal  of  the  injured  part 
may  benefit  the  patient — Quenu).  The  nature  of  this  toxine  is 
not  definitely  established,  but  it  is  supposed  to  be  a  nitrogenous 
derivative  of  killed  tissues.  Thus  Dale  and  Laidlaw  showed  that 
"histamine,"  a  proteid  cell  derivative,  may  produce  a  very  similar 
state.  It  does  not  cause  fall  in  arterial  blood  pressure  by  vasomotor 
paralysis,  but  by  capillary  dilatation,  which  may  be  so  great  as  to 
leave  the  heart  nearly  empty.  This  same  condition  seems  to  exist 
in  wound  or  surgical  shock.  N.  M.  Keith  showed  that  by  intro- 
ducing an  insoluble  dye  and  after  an  interval  determining  its 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    311 

detention,  the  circulating  blood  may  be  reduced  in  these  cases  to 
a  little  more  than  half  the  normal.  Treatment  consists  in  restoring 
the  blood  volume  by  an  intravenous  fluid,  not  by  saline  which  is 
rapidly  lost  from  the  circulation,  but  with  a  colloid  with  osmotic 
pressure,  such  as  gelatine  or  gum  acacia  (Bayliss). 

Not  all  cases  of  so-called  shock  can  be  explained  on  this  basis. 
Intense  peripheral  irritation  (pain),  especially  if  spread  over  a 
wide  area,  causes,  through  reflex  exaggeration  of  central  impulses, 
what  may  be  termed  ganglion  cell  exhaustion  and  gives  rise  to 
shock  by  central  disassociation  or,  as  Meltzer  believes  preponder- 
ance of  inhibition  (burns,  trauma,  etc.) 

Henderson  assumes  shock  as  being  due  to  the  forced  respiration 
which  follows  violent  trauma.  This  liberates  a  large  amount  of 
CC>2  from  the  tissues  and  gives  rise  to  "acapnia,"  a  condition  in 
which  the  normal  amount  of  carbon  dioxide,  which  is  essential  to 
stimulation  of  the  respiratory  center,  is  gradually  exhausted.  The 
individual,  therefore,  dies  from  lack  of  oxygen,  as  the  respiratory 
center  remains,  from  want  of  carbon  dioxide,  inactive.  But,  it  is 
very  doubtful  whether  "acapnia"  is  ever  an  essential  cause  of 
shock.  H.  H.  Janeway  and  E.  M.  Ewing  believe  that  the  shock 
produced  in  animals  by  artificial  forced  respiration  is  due  to  the 
prevention  of  flow  of  blood  from  the  veins  into  the  heart,  and  shock 
may  occur  with  high  CC>2  contents  in  the  body. 

Shock  is  generally  associated  with  so-called  "acidosis,"  that  is, 
a  marked  decline  in  alkali  reserve  in  the  body.  But  acidosis  is 
generally  associated  with  low  blood  pressure  and  also  occurs  in 
agony,  so  that  it  is  not  likely  a  cause,  but  rather  the  result  of  shock. 

DISTURBANCES  IN  LYMPH  CIRCULATION  (Pathological  Transuda- 
tion).  The  pathological  disturbances  in  lymph  circulation  are 
intimately  associated  with,  and  greatly  dependent  upon  the  blood 
circulation.1  In  order  to  understand  the  pathological  variations  in 

1  It  is  still  customary  to  distinguish  between  transudates  and  exudates;  the 
transudate  is  a  non-inflammatory  discharge  of  modified  serum  into  tissues 
(lymph),  the  exudate  is  an  inflammatory  product  which  more  or  less  closely 
resembles  plasma  and  contains  blood  cells  in  varying  proportions.  Between 
the  two  lie  all  sorts  of  gradations.  Those  fluids  which  still  retain  some  char- 
acters of  transudate  (very  fluid)  and  at  the  same  time  possess  others  of  exudates 
(cell  contents,  much  albumen)  are  spoken  of  as  inflammatory  edema. 


312  GENERAL  PATHOLOGY 

transudation  (lymph  production)  and  in  the  relations  of  blood  and 
lymph  circulation,  it  is  necessary  to  have  a  clear  conception  of  the 
physiological  interchange  between  blood,  lymph  and  tissues. 
Between  them  occurs  normally  an  active  exchange  of  fluid,  nutri- 
tive material  (colloids  and  crystalline  substances)  and  gases  (O  is 
taken  up  by  tissues,  CO2  is  given  off).  Into  this  interchange  enter 
filtration  (blood  pressure)  and  diffusion  through  vascular  mem- 
branes of  gases,  soluble  salts  and  colloids  (proteins),  according  to 
the  laws  of  osmosis. 

It  was  formerly  held  that  the  living  endothelium  exercised  a 
selective  secretory  activity  (vital  act).  We  know  to-day  that  the 
endothelium  is  of  importance  only  in  so  far  as  it  determines  the 
constitution  of  the  osmotic  membrane.  Dialysis  does  not  depend, 
as  formerly  accepted,  upon  crystalline  or  non-crystalline  nature  of  a 
substance,  but  upon  affinity  for  the  septum  employed.  In  other 
words,  osmosis  is  due  to  solvent  action  of  the  membrane,  and  the 
constitution  of  the  membrane  and  solubility  in  that  membrane  of 
the  solutes  on  either  side  of  it  are  the  all-important  factors  in 
determining  whether  and  how  diffusion  shall  obtain. 

Thus  Kahlenberg  used  in  his  experiments  on  osmosis  septa  of 
pure  rubber  and  various  fluids  as  solvents,  the  most  striking  results 
being  obtained  with  pyridine.  With  pyridine  alone  on  one  side  of 
the  septum,  but  with  the  same  medium  containing  cane  sugar  and 
copper  oleate  on  the  other,  it  was  found  that  the  colloid  copper 
oleate  passed  freely  through  the  septum,  but  the  crystalline,  cane 
sugar,  remained  behind.  When,  on  the  other  hand,  two  crystal- 
loids, camphor  and  cane  sugar,  were  in  solution  in  pyridine,  the 
camphor,  but  again  not  the  cane  sugar,  passed  through  the  mem- 
brane. Kahlenberg  was  able  later  to  obtain  similar  "selective" 
osmosis  in  colloids.  Copper  oleate  in  benzine  which  passes  through  a 
rubber  septum,  does  not  pass  through  parchment. 

The  constitution  of  the  capillary  membrane  is  influenced  by  the 
surrounding  fluids,  one  an  internal,  arterial,  more  or  less  uniform 
in  composition,  the  other,  an  external  variable  which  is  derived 
for  the  tissues. 

The  difference  in  tissue  fluids,  which  is  due  to  the  qualitative 
functional  differences  of  cells  in  various  organs,  determines  largely 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    313 

the  local  diffusion  permeability  of  the  capillary  membrane,  so  that 
different  cell  territories  (organs)  possess  specific  diffusion  proper- 
ties in  their  capillary  membranes.  This  constitutes  the  so-called 
selective  property  in  the  diffusion  function  of  the  capillary  mem- 
brane in  different  organs.  The  force  in  the  fluid  interchange  between 
blood  and  tissue  is  the  hydrostatic  pressure  difference  (filtration 
pressure).  Periodicity  in  certain  organ  functions  depends  appar- 
ently upon  temporary  differences  in  diffusion  permeability 
(reversible  properties  of  colloidal  membranes). 

These  factors  determine,  then,  what  is  to  pass  through  a  vascular 
membrane,  i.e.,  the  character  of  a  transudate,  into  tissue  spaces  and 
lymph  vessels,  and  vice  versa.  Besides  these,  however,  the  water 
and  solid  contents  of  the  cells  themselves  depend  upon  their  own 
colloidal  state  and  osmotic  pressure,  and  in  these  two  rests  the 
ability  of  cells  to  take  up  and  retain  water  and  nutriment  (see 
above  under  Parenchymatous  Degeneration  and  Hypertrophy). 
The  removal  of  the  transuded  material  which  has  been  changed 
by  the  metabolism  of  the  tissues  with  which  it  has  been  in  contact, 
is  accomplished  through  tissue  spaces  which  empty  into  lymphatics 
and  through  these  into  the  thoracic  duct.  The  latter  carries,  there- 
fore, substances  for  nutrition  (from  gut)  as  well  as  for  elimination. 
Removal  and  motion  of  lymph  depends  upon  the  capillary  pressure, 
activity  of  organs  (especially  in  muscles)  and  tissue  tension.  The 
physiological  transudate  is  isotonic  to  blood,  corresponds  to 
about  a  0.9  per  cent.  NaCI  solution,  but  is  poorer  in  proteins  and 
does  not  coagulate  spontaneously.  Blood  cells  do  not,  under  normal 
conditions,  enter  lymphatics. 

The  most  frequent  and  important  pathological  variation  in  the 
process  of  transudation  is  the  local  or  general  accumulation  of 
fluid  in  the  tissues  (spaces  and  cells)  and  is  known  as  edema.  In 
the  skin  it  is  referred  to  as  anasarka,  in  body  cavities  as  hydrops. 
Other  nomenclature  expresses  its  location;  hydropericardium, 
hydrothorax,  hydrocephalus,  hydrarthros,  etc.  Edema  results 
from  a  disproportion  in  the  factors  determining  transudation, 
water  contents  in  tissues  and  resorption.  What  is  the  mechanism 
of  this  disproportion?  First,  increased  filtration  from  increased 
permeability  in  vessel  walls  (nutritive  or  toxic  injury)  with  changes 


314  GENERAL  PATHOLOGY 

in  blood  pressure.  Especially  important  is  here  low  arterial  and 
high  venous  pressure.  Increased  arterial  pressure  does  not  by  itself 
materially  influence  fluid  in  tissues  (see  below  under  edema  from 
Circulatory  Causes).  Second,  increased  fluid  imbibition  of  tissues 
from  augmented  osmotic  pressure  in  cells.  This  results  from  any 
cause  which  diminishes  oxidation  and  from  accumulation  of 
metabolic  or  disintegration  products  (nutritive  or  toxic  tissue 
asphyxia).  Higher  osmotic  pressure  in  tissues  than  in  blood  and 
lymph  also  tends  to  increase  transudation  from  blood  into  tissues. 
Intimately  associated  is  increased  H  ion  concentration  (acidity) 
which  leads  to  increased  hydration  capacity  of  cells.  Third,  lessened 
resorption  by  lymphatics;  this,  like  increased  transudation  from 
blood  vessels,  depends  upon  nutritive  or  toxic  injury  of  their 
endothelial  membrane  which  diminishes,  and,  in  some  cases  prob- 
ably entirely  suspends  their  resorptive  capacity.  It  will  be  ap- 
parent that  a  concerted,  combined  action  of  these  factors  must 
be  the  rule,  inasmuch  as  conditions  leading  to  changes  in  one  will 
generally  lead  to  changes  in  the  others.  Certain  it  is  that  the  edema- 
tous  fluid  accumulates  first  in  the  tissue  spaces  and  then  is  taken 
up  by  the  cells.  Increased  transudation  alone  is  not  able  to  produce 
edema,  as  the  fluid  is  readily  removed  from  healthy  tissues  by 
intact  lymphatics. 

Edema  may  be  classified  according  to  the  underlying  causes,  as 
follows : 

(a)  Edema  Due  to  Circulatory  Disturbances.  Arterial  hyperemia 
itself  never  leads  to  edema,  for  although  transudation  may  be 
increased,  this  is  fully  compensated  for  by  increased  lymphatic 
resorption.  Edema  follows  only  when  arterial  hyperemia  is 
combined  with  certain  stimuli  which,  by  lesion  of  tissues  and  lym- 
phatics, interfere  with  cell  activity  and  water  resorption  (inflam- 
matory edema — first  stage  of  exudate).  Venous  hyperemia  is,  on 
the  other  hand,  a  very  frequent  cause  of  edema,  either  from 
prolonged  general  venous  congestion  or  from  local  reasons.  Here 
a  number  of  processes  are  involved.  First,  increased  venous  capil- 
lary pressure  (low  arterial  pressure)  and  nutritive  interferences 
with  the  lining  endothelial  membranes  in  blood  and  lymph  system. 
Secondly,  increase  in  osmotic  pressure  in  tissues  from  lessened 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    315 

oxidation  and  accumulation  of  metabolic  products,  with  increase 
in  H  ion  concentration.  Both  tend  to  increase  the  amount  of 
transudate  and  at  the  same  time  favor  its  detention  in  the  tissues. 
Vascular  edema  generally  follows  gravity,  occurring  first  in  depen- 
dent parts. 

(b)  Edema  Due  to  Toxic  Influences.  This  finds  its  origin  in  the 
action  of  poisons  (toxines)  on  blood  vessel  walls,  tissues  and 
lymphatics.  These  may  be  inorganic  (uranium,  arsenic,  trinitrotol- 
uene), organic  (cantharidine),  bacterial,  or  metabolic  (edema  of 
anaphylaxis,  urticaria  after  eating  certain  foods). 

Closely  related  to  these  toxic  edemas  are  those  occurring  in 
certain  forms  of  nephritis.  In  some  they  are  seen  very  early  in  the 
disease  (severe  degenerative  and  exudative  nephritis,  especially 
in  scarlet  fever).  They  make  their  appearance,  unlike  vascular 
edema,  in  loose  tissues  quite  irrespective  of  gravity  (eyes,  scrotum, 
etc.).  Nephritic  edema  must  be  attributed  to  direct  injurious 
effects  of  those  toxines  which  excite  the  inflammation  of  the  kidney 
upon  blood  and  lymph  circulation  and  tissues.  This  action  is  more 
or  less  selective  and  similar  to  that  of  certain  other  inorganic 
poisons.  Thus  uranium  and  trinitrotoluene  produce  a  nephritis 
with  marked  general  edema,  while  the  nephritis  produced  by 
administration  of  chromium  salts  goes  along  without  any  edema 
(absence  of  specific  vascular  irritants) .  Furthermore,  the  serum  of 
edematous  nephritis  is  capable  of  inducing  an  increased  lymph  flow 
when  injected  into  animals  (Kast  and  Starling).  Nephritic  edema 
is,  therefore,  an  example  of  "edema"  or  "hydrops  irritativus." 

The  edema  of  nephritis  is  very  apt  to  increase  and  spread  very 
generally.  In  these  advancing  cases,  other  new  factors  aid  in  its 
continuance;  one  is  the  hydremic  plethora,  the  relative  increase 
of  watery  elements  in  the  blood  as  a  result  of  diminished  water 
excretion  in  many  of  these  cases.  This  blood  thinning,  of  course, 
aids  transudation.  The  other  factor  seems  to  be  a  retention  of 
NaCI,  which  requires  water  to  maintain  osmotic  pressure.  But 
it  must  be  considered  that  the  retention  of  NaCI  may  also  be,  at 
least  partly,  influenced  by  the  edema  itself,  which  is  a  salt  solu- 
tion. In  any  event  these  last  two  can  only  be  held  contributory, 
not  causative.  Late  in  nephritis  toxic  edema  may  combine  with 


316  GENERAL  PATHOLOGY 

vascular    edema    from    gradually    declining    circulation    (heart 
weakness). 

(c)  Neuropathic  Edema.     Irritation  of  vasodilators  or  paralysis 
of  vasoconstrictors  may  be  followed  by  edema.  It  occurs  in  a 
number  of  nervous  lesions  (from  local  nutritional  disturbances?), 
which  generally  accompany  trophic  changes. 

(d)  Edema  of  cachexia  and  in  atrophic  senile  tissues  is  only 
moderate  and  due  to  a  number  of  local  tissue  changes  which  pre- 
vent proper  removal  of  transudate. 

It  is  apparent  from  what  has  been  presented  that  not  infre- 
quently a  number  of  causes  underlie  the  production  of  edema  in  an 
individual  case,  most  frequently  a  combination  of  toxic  and  circu- 
latory disturbances. 

Edematous  parts  are  swollen,  anemic,  doughy,  and  of  markedly 
diminished  elasticity.  The  edematous  transudate  is  light  yellow, 
clear,  of  low  specific  gravity  (1006  to  1012)  and  of  low  protein  con- 
tents (0.7  to  4  per  cent.).  Inflammatory  exudates  have  a  specific 
gravity  of  1018  to  1020,  and  a  protein  content  of  always  over  4 
per  cent.  Transudates  do  not  coagulate  spontaneously,  except 
after  long  retention  in  cavities.  Their  salt  contents  correspond  to 
those  of  the  blood,  sometimes  they  are  increased.  They  also  con- 
tain other  crystalline  blood  solvents. 

Results  of  Edema.  Edema  necessarily  interferes  with  functions 
of  tissues  and  may  also  produce  serious  mechanical  consequences 
from  the  mere  accumulation  of  fluid  (pressure  on  heart  or  lung 
from  fluid  in  pericardium  and  pleura,  etc.).  Even  larger  veins 
may  be  compressed.  Microscopically  cells  and  outer  cell  spaces 
are  seen  to  enlarge,  widen,  separate  and  become  turbid  and  hazy. 
Later  they  undergo  solution  (see  Cytolytic  Necrosis).  CoIIagenous 
connective  tissue  fibrils  swell  markedly  and  separate.  In  chronic 
inveterate  edema  tissues  become  hard,  thick  and  entirely  inelastic. 

II.    DISTURBANCES     OF     INTERNAL     SECRETION     AND     OF     SPECIFIC 

METABOLISM 

The  disturbances  of  internal  secretion  will  be  considered  in 
this  connection  only  in  their  general  aspects  and  relations,  for 
a  detailed  study  of  the  various  diseases  resulting  from  patho- 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    317 

logical  changes  in  individual  organs  of  internal  secretion  belongs,  of 
course,  to  special  or  systemic  pathology. 

All  organs  possess,  in  one  sense,  an  internal  secretion,  inasmuch  as 
they  discharge  into  blood  and  lymph  specific  products  of  their  metab- 
olism. These  are,  first,  finished  end  products  which  are  removed 
from  the  body  by  the  lungs,  the  kidney,  the  skin  and  the  gut.  Sec- 
ondly, intermediary  products  which  are  carried  from  one  organ 
to  another  for  final  disposition,  oxidation,  synthesis,  hydration,  etc. 
Thirdly,  specific  products  of  cell  activity,  internal  secretions  in 
the  strict  sense,  which  circulate  in  the  body  and  exert  definite, 
specific  actions  on  cells  of  certain  territories,  stimulating,  modifying 
or  inhibiting  their  functional,  nutritive  or  formative  activities. 
Such  secretions  which  fulfill  the  duties  of  messengers  from  one 
tissue  to  another  are  termed  by  Starling  hormones  (fromopjudm*/  = 
to  excite).  The  action  of  hormones  appears  to  be  chemical  and  due 
to  biochemical  affinity  and  relations  of  the  secretions  of  one  organ 
to  the  cells  of  another.  It  is  likely  that  all  organs  in  the  body  are 
hormone  producers  and  that  the  organic  union  of  the  body  is 
brought  about  by  hormone  action.  There  exist,  however,  in  all 
higher  vertebrates  certain  glandular  organs,  so  called  ductless 
glands,  which  are  spoken  of  as  organs  of  internal  secretion  in  a 
strict  sense,  or  endocrine  (evdov  =  within,  Ksvveiv  =  to  separate) 
glands.  These  possess  important  specific  secretions  adapted  for  a 
particular  tissue  soil  and  stand  amongst  each  other  in  close  rela- 
tions of  augmentation  or  antagonism.  They  seem,  moreover,  en- 
dowed with  specific  metabolic  duties  in  regulating  the  secretions 
of  each  other.  These  organs  are  derived  from  glands  all  of  which 
originally  possessed  an  external  as  well  as  an  internal  secretion, 
but  which  through  evolutionary  changes  became  dislocated  and 
lost  their  external  secretion  while  the  necessity  for  reciprocal 
internal  relations  with  a  particular  tissue  soil  continued  and 
developed. 

When,  on  the  other  side,  evolutionary  changes  destroyed  the 
necessity  for  external  secretion  and  at  the  same  time  removed  any 
tissue  which  had  affinity  for  a  particular  internal  secretion,  these 
organs  or  glands  atrophied,  disappeared,  or  were  only  recapitulated 
in  an  abbreviated  or  rudimentary  form  which  was  adapted  to  the 


3i8  GENERAL  PATHOLOGY 

organization  of  an  age  period.  Thus  it  happens  that  thyroid,  hy- 
pophysis and  chromaffinic  system  persisted  as  permanent  organs  of 
internal  secretion,  although  they  no  longer  contribute  any  external 
secretion  and  are  divorced  from  their  original  glandular  connec- 
tions. The  thymus,  mesonephros  and  lymphoid  system  are  only  com- 
patible with  certain  early  age  periods,  while,  finally,  pancreas, 
placenta,  kidneys  and  liver  still  maintain  external  as  well  as  internal 
secretions  and  specific  metabolic  activities  (see  below  under  Pan- 
creas, in  Diabetes  and  Suprarenal  Gland). 

In  this  evolution  of  organs  of  internal  secretion  we  already  noted 
that  the  interaction  of  organs  and  tissues  is  by  no  means  always  al- 
truistic, but  frequently  antagonistic,  even  destructive.  Embryonic 
development  and  infancy  show  these  relations  more  prominently 
than  later  life.  Boll  and  Roux  speak  of  this  in  more  or  less  personal 
manner  as  "the  struggle  of  tissues"  or  "the  battle  of  the  parts." 
Thus  the  disappearance  of  certain  embryonic  structures,  such  as  the 
mesonephros,  depends  upon  antagonistic  action  of  the  growing  sex 
gland,  which  consumes  most  of  it  and  incorporates  certain  remain- 
ing parts  for  its  own  purpose.  Similar  factors  are  at  play  in  the  dis- 
appearance of  other  tissues  and  organs  from  fetal  life  to  senility — 
thymus,  spleen,  lymphoid  tissues,  etc.  (see  under  Disposition). 

Hormone  action  is,  therefore,  in  its  altruistic  and  opposing 
forces  a  strong  factor  in  normal  as  well  as  abnormal  life  and 
depends  upon  reciprocal  biochemic  relations  between  organs  or 
tissue  territories. 

Our  knowledge  of  the  disorders  of  internal  secretion  may  prop- 
erly be  said  to  begin  with  the  important  discovery  by  Addison  of  a 
disease  which  is  characterized  by  marked  asthenia  (low  blood  pres- 
sure) and  bronze  pigmentation  of  skin  and  mucous  membrane,  and 
associated  with  pathological  changes  in  the  suprarenal  glands. 
This  was  followed  by  the  discovery  of  adrenalin  or  epinephrin, 
an  internal  secretion  of  the  chromaffin  cells  in  the  medulla  of  the 
adrenal,  which  possesses  a  marked  stimulating  effect  on  the  vas- 
cular tonicity  and  pigment  metabolism.  This  knowledge  of  inter- 
nal secretion  was  very  soon  enlarged  by  growing  experience  in 
regard  to  function  of  other  glands,  notably  the  thyroid,  the  thymus, 
hypophysis  cerebri,  testicle,  ovary  and  pancreas.  Quite  recently  the 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS  319 

augmenting  or  antagonistic  relations  of  these  organs  have  been 
matters  of  investigation,  but  much  still  remains  unknown  or 
more  or  less  speculative. 

Disturbances  of  internal  secretion  may  be  classified  in  a  general 
way  as  follows:  (i)  Afunction;  results  when  the  action  of  a  gland 
is  abolished  either  from  congenital  loss  or  from  disease  (thus  in 
the  thyroid  it  leads  to  myxedema,  cretinism;  in  the  suprarenal  to 
Addison's  syndrome,  etc.).  (2)  Hypofunction;  results  from  insuffi- 
cient secretion  in  under-development  or  after  gland  exhaustion 
(results  to  be  noted  in  secretion  of  testicle  or  ovary) .  (3)  Hyper- 
function;  results  from  hypersecretion  in  hypertrophy  or  glandular 
tumors  of  organs  of  internal  secretion  (thus  results  Graves'  dis- 
ease, in  goiter,  increased  nitrogen  metabolism  in  the  same  disease; 
giantism  or  acromegaly  in  tumors  of  hypophysis,  etc.).  (4)  Dys- 
function; or  perverse  function,  is,  as  yet,  very  little  understood. 
It  may  result  from  disease  of  the  glandular  cells  or  may  be  due  to 
pathological  changes  in  the  receptive  soil  or  changes  which  the 
secretion  undergoes  by  passage  through  diseased  organs. 

But  internal  secretion  is  apparently  not  the  only  important 
function  of  endocrine  glands,  through  which  they  modify  activity 
of  other  organs  and  tissues.  Some  of  them,  at  least,  possess  specific 
metabolic  functions  for  the  regulation  of  secretions  and  metabolic 
products  of  other  glands.  Toxic  substances  which  originate  in  the 
so-called  intermediary  metabolism,  unless  they  are  either  rapidly 
eliminated  or  oxidized  or  combined  with  other  substances  to 
form  non-poisonous  products,  are  thus  taken  care  of.  Such  a 
detoxicating  function  is  exercised  by  the  kidney  and  liver  and 
possibly  also  by  the  cortex  of  the  suprarenal  gland.  But  it  is  also 
likely  that  in  this  way  the  internal  secretions  are  themselves  regu- 
lated. This  has  been  made  probable  for  the  pancreas  in  diabetes. 
Recent  experimental  investigations  by  Milne  and  Peters  indicate 
that  the  role  of  the  pancreas  in  diabetes  is  not  connected  with  the 
disturbance  of  an  internal  secretion  for  combustion  of  sugar 
for  the  ability  of  the  tissues  to  take  up  and  burn  sugar  and  to 
convert  sugar  into  glycogen  is,  as  results  in  depancreatized  dogs 
show,  not  diminished  in  diabetes.  If  now  the  tissues  in  diabetes 
can  utilize  dextrose,  and  since  their  glycogen  content  is  usu- 


320  GENERAL  PATHOLOGY 

ally  reduced,  the  disease  would  seem  to  depend  upon  an  excessive 
production  of  glucose  from  glycogen.  And  this  view  is  strengthened 
by  the  observation  that  in  such  animals  the  diastatic  action  of  the 
serum  (conversion  of  glycogen  into  sugar)  is  found  at  times 
markedly  increased,  but  always  somewhat  so.  This  increased  sugar 
conversion  may  be  the  result  of  failure  of  secretion  of  an  anti- 
diastatic  enzyme,  or,  as  seems  more  probable,  due  to  the  action  of 
accumulative  substances  in  the  serum  which  normally  should  be 
destroyed  or  altered  by  the  pancreas. 

This  mechanism  of  metabolic  interaction  and  regulation  of 
hormone  secretions  is  an  illustration  of  one  of  the  methods  by  which 
endocrine  glands  enter  into  mutual  relationship  and  through  dis- 
turbances of  which  pathological  states  may  ensue.  On  the  other 
hand,  it  appears  equally  true  that  a  hyperactivity  of  endocrine 
glands  must  also  exert  a  powerful  and  modifying  influence  on  the 
functions  of  another  gland  with  which  they  are  biochemically  inti- 
mately connected.  Thus,  thyroid  hyperactivity  seems  to  stimulate 
the  secretion  of  the  suprarenal  gland,  and  we  find  in  Graves' 
(Basedow's)  disease  with  marked  thyroid  hyperplasia  an  increase 
of  adrenalin  in  the  blood.  Again,  thyroid  hypersecretion  may  inter- 
fere with  the  metabolic  activities  of  the  pancreas  and  lead  to  gly- 
cosuria  and  it  may  increase  nitrogen  metabolism.  A  very  close 
relation  also  exists  between  thymus  and  thyroid.  The  most  severe 
cases  of  thyroidism  (Graves'  disease)  show  also  thymus  involve- 
ment in  enlargement  and  hyper  or  perverse  secretion,  and  it  is  certain, 
although  we  know  as  yet  nothing  definite  of  the  exact  mechanism 
of  the  relation  of  thyroid  to  thymus  and  of  the  functional  activity  of 
the  thymus,  that  many  of  the  symptoms  and  lesions  in  exoph- 
thalmic goiter  or  Graves'  or  Basedow's  disease  are  of  thymus 
origin,  or,  at  least,  that  both  thyroid  and  thymus  respond  to  one 
common  etiological  factor  which  alters  their  structure  and  disturbs 
their  function. 

It  will  have  been  seen  that  the  subject  of  internal  secretion  is  one 
which  is  as  yet  not  fully  understood  in  all  its  physiological  aspects 
and  ramifications  and  that  its  pathological  changes,  although  far 
reaching,  remain  at  present  more  or  less  speculative. 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    321 

in.  FEVER.  (FEBRIS.  PYREXIA) 

Very  generally,  disturbances  of  organ  interrelations,  more 
especially  those  which  depend  upon  infection,  are  associated  with 
disturbances  in  body  temperature.  Normal,  physiological  proc- 
esses are,  by  reason  of  their  chemical  and  physical  nature,  heat 
producers.  Especially  muscle  and  gland  activity  generates  heat  and 
the  amount  of  heat  thus  produced  raises  the  body  temperature  in 
one  hour  about  i°C.  This  heat  production  is  compensated  by  heat 
dissipation  through  skin,  lungs,  feces  and  urine.  A  proper  correla- 
tion of  heat  production  and  dissipation,  regulated  by  certain 
nervous  centers,  establishes  a  fairly  even,  normal,  body  temperature 
ranging  between  37.2°  and  37.4°  C.  But  even  under  normal  conditions 
fluctuations  occur;  it  is  lower  in  the  morning  than  in  the  evening, 
the  difference  amounting  to  i°  to  i.5°C.  If  the  environment  of  the 
body  is  cold,  the  heat  production  goes  up  and  heat  dissipation  is 
lowered  (contraction  of  skin  vessels,  no  perspiration).  On  the  other 
hand,  when  the  environmental  temperature  rises,  heat  production 
is  reduced  and  heat  dissipation  augmented  (through  respiration 
and  perspiration).  Thus  the  nervous  regulatory  mechanism  keeps 
temperature  at  an  even  level.  But  this  mechanism  has  its  limits 
of  endurance  and  may  be  upset.  In  heat  stroke,  for  example,  heat 
dissipation  cannot  keep  pace  with  heat  production  and  in  freezing 
no  amount  of  heat  production  is  able  to  compensate  the  loss. 

A  great  number  of  diseases  which  depend  upon  foreign  invasion 
display  a  peculiar  upset  in  this  regulatory  mechanism  in  favor  of 
heat  production  over  heat  dissipation,  and  this  is  known  as  fever. 
Fever  is  a  more  lasting  upset  of  this  regulation  and  balance,  and 
to  be  differentiated  from  a  temporary  disarrangement  in  body  heat 
such  as  may  occur  as  a  result  of  severe  exercise.  Characteristic  of 
fever  is  then  a  permanent  rise  in  temperature,  morever,  one  with 
which  are  associated  other  constitutional  disturbances  such  as  in- 
crease in  pulse  rate,  vasomotor  phenomena  shown  by  an  uneven 
blood  distribution  in  the  body,  changes  in  the  gaseous  exchange  and 
in  urine  secretion,  nervous  disturbances,  headache,  delirium,  etc.; 
These  accompanying  processes  are  partly  due  to  the  febrile  state, 

but  probably  largely  to  the  underlying  causes  of  the  fever  (toxines, 
21 


322  GENERAL  PATHOLOGY 

etc.).  They  are,  therefore,  correlated  with  and,  at  least  not  en- 
tirely, dependent  upon  the  febrile  state. 

The  fever  process  may  be  divided  into  three  periods : 

First:  Initial  stage,  stadium  incrementi.  Here  temperature  rises 
from  normal  to  height  of  the  febrile  temperature.  It  varies  in 
time,  may  be  short  (J^  hour)  to  several  hours.  It  is  then  usually 
associated  with  rigors  or  definite  chills.  When  the  stadium  in- 
crementi is  long,  extending  over  days,  only  rigors  or  chilly  sensa- 
tions are  experienced. 

Second:  Fastigium  is  the  acme,  apex,  of  temperature  rise  and  is 
generally  maintained  unevenly,  with  remissions.  These  remissions 
may  be  more  or  less  regular,  often  in  characteristic  temporal 
sequence  (see  below). 

Third:  Defervescence,  stadium  decrementi.  Here  the  tempera- 
ture returns  to  normal,  either  rapidly,  by  crisis,  or  gradually, 
by  lysis.  The  crisis  is  usually  attended  by  profuse  perspiration  and 
the  temperature  sinks  in  a  few  hours  to  one-half  of  a  day  from  2°  to 
6°C.  In  lysis  the  decline  of  temperature  generally  extends  over  days 
and  is  either  continuous  or  intermittent.  After  permanent  return  to 
normal,  the  individual  is  said  to  be  convalescent. 

Fevers  are  frequently  classified  according  to  the  manner  in 
which  temperature  rises  and  is  maintained  during  fastigium.  If  the 
daily  variations  between  minimum  of  morning  and  maximum  of 
evening  are  not  essentially  greater  than  corresponding  normal 
variations,  the  fever  is  known  as  "febris  continua."  If  greater 
differences  are  noted  between  morning  and  evening  and  between 
days,  it  is  "febris  remittens."  If  between  febrile  periods  occur 
stretches  of  apyrexia  (normal  temperature),  it  is  "febris  intermit- 
tens"  and  that  may  be  regular  or  irregular.  Finally,  when  after  a 
sudden  rise  which  continues  for  a  period  of  time,  an  equally  sudden 
fall  occurs,  which  is  followed  by  an  afebrile  period,  to  reappear  and 
go  repeatedly  through  the  same  performance,  it  is  "febris  recurrens." 
Combinations  of  these  febrile  types  are  frequent,  thus  continuous 
and  remittent,  in  typhoid,  etc.,  intermittent  and  remittent,  in 
septicemia,  etc. 

These  expressions  and  courses  of  fever  depend  essentially  upon 
definite  interactions  between  invader  and  host.  Thus,  the  rise  in 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS  323 

temperature  is  incident  to  generalization  of  the  infection,  the  fall 
to  either  temporary  or  permanent  annihilation  of  its  forces.  In 
malaria,  for  example,  chill  and  fever  fall  together  with  the  time  of 
discharge  of  merozoites  from  red  blood  cells  into  the  circulation, 
and  the  fever  is  maintained  until  they  have  disappeared  to  renew 
their  cycle  in  red  blood  cells.  In  the  remittent  fever,  due  to  the 
spirillum  of  Obermeier,  the  entrance  of  the  spirillum  into  the  circu- 
lation is  coincident  with  the  fever;  its  regression  into  the  bone 
marrow,  and  disappearance  from  the  general  body  corresponds  to 
the  intervening  afebrile  periods.  Thus  also,  in  pneumonia  the 
sudden  crisis  goes  along  with  the  disintegration  and  sudden  resolu- 
tion of  the  inflammatory  exudate  in  the  lung.  Other  infections  in 
which  such  sharp  reactions  between  invader  and  host  do  not  occur, 
show  a  much  less  characteristic  fever  curve. 

The  fever  patient  presents  subjective  and  objective  fever  signs 
and  symptoms.  In  the  first  stage  he  is  cold  and  the  skin  is  cold  to 
touch  (lessened  heat  dissipation  with  rising  temperature).  In 
fastigium  uneven  heat  dissipation  is  generally  noticeable  objec- 
tively and  subjectively.  The  skin  is  irregularly  reddened,  in 
parts  hot,  in  others  cool  (vasomotor  disturbances).  Extremities 
are  especially  apt  to  be  colder  than  the  rest  of  the  body.  In  defer- 
vescence skin  vessels  dilate  generally,  normal  circulation  is  re- 
established and  ushered  in  by  perspiration  (increase  in  heat 
dissipation). 

The  problem  of  fever  centers  in  two  questions:  (i)  Causes  of 
fever  and  of  the  rise  in  temperature.  (2)  The  nature  and  significance 
of  fever. 

i.  Cause  of  Fever  and  of  the  Rise  in  Temperature.  The  exact, 
immediate  cause  of  fever  is  not  clear,  but  it  is  known  that  certain 
foreign  substances  (especially  proteids,  but  also  purin  bases,  caffeine, 
etc.),  when  introduced  into  the  body  or,  when  originating  within 
the  body,  upset  the  central  heat  regulating  mechanism.  There 
are  also  mechanical  traumatic  injuries  of  the  brain  and  nervous 
diseases  which,  possibly  by  direct  irritation  of  heat  centers, 
lead  to  high  fever.  The  mechanism  of  this  pathological  upset  in 
body  temperature  is  stimulation  of  certain  heat-producing  func- 
tions coupled  with  inhibition  of  heat  dissipation.  This  becomes 


324  GENERAL  PATHOLOGY 

irregular  and  loses  its  normal  coordination  with  heat  produc- 
tion. Experimental  investigation  has  located  the  center  of  heat 
regulation  in  higher  animals  within  the  corpus  striatum.  Injury 
or  electrical  stimulation  of  this  center  leads  not  only  to  the  rise 
of  temperature,  but  also  to  the  increased  gaseous  exchange  and  in- 
creased nitrogenous  metabolism  characteristic  of  fever.  But  fever 
is  also  possible  in  cold-blooded  animals  which  do  not  possess  a 
nervous  regulatory  mechanism,  so  that  fever  may  arise  from  gen- 
eral toxogenic  influences. 

Experiments  have  conclusively  demonstrated  that  in  all  feverish 
processes  oxidation  and  tissue  disintegration  are  increased  so  that 
O  consumption  as  well  as  CO2  elimination  are  higher  than  normal. 
This  rise  may  be  20  times  the  normal.  Nitrogen  excretion  is  in  ex- 
cess of  that  of  food  intake  due  to  toxic  destruction  and  fusion  of 
body  tissues.  It  appears  that  it  is  derived  from  the  disintegration  of 
nitrogenous  elements  of  cell  protoplasm  and  this  is  the  important 
source  of  heat  in  fever  as  contrasted  with  the  normal  source  from 
carbohydrates  and  fats. 

Dissipation  of  heat  is  also  increased,  but  not  in  proportion  to 
oxidation  and  waste  of  tissues,  moreover  it  is  irregular,  and  rela- 
tively insufficient,  consequently  the  temperature  of  the  body  rises. 
It  has  been  held  by  Senator  that  active  molecular  disturbances  and 
rearrangements  in  cell  protoplasm  may  be  an  additional  source  of 
heat  in  fever.  The  associated  constitutional  disturbances,  subjec- 
tive sensations  and  objective  findings  (parenchymatous  degenera- 
tion) are  probably,  at  least  largely,  of  toxic  origin  (exogenous  and 
endogenous  from  tissue  destruction)  and  only  partly  dependent 
upon  the  temperature  (vasomotor  disturbances,  increased  pulse 
rate,  general  depression,  delirium,  coma).  Death  occurs  in  very 
high  temperatures  (hyperpyrexia)  from  heart  insufficiency  (vaso- 
motor paralysis).  Here  again  the  toxic  influence  seems  more  re- 
sponsible than  the  temperature  alone. 

2.  Nature  and  Significance  of  Fever.  It  has  already  been  stated 
that  most  fevers  are  intimately  associated  with  the  interactions  of 
the  body  and  an  invader.  Here  the  fever  temperature  undoubtedly 
accelerates  and  improves  immunity  reactions  and  the  destruction 
of  bacteria  is  more  readily  accomplished  in  fever  temperatures. 


CHANGES  IN  GENERAL  CELL  INTERRELATIONS    325 

Generally  speaking,  therefore,  fever  temperature  is  rather  helpful 
and  beneficial,  but  it  must  be  remembered  that  the  mechanism  of 
its  production,  especially  in  heat  production  from  tissue  disinte- 
gration, not  as  normally  from  fats  and  carbohydrates,  is  dangerous 
and  by  no  means  a  beneficial  process  for  the  organism. 


CHAPTER  V 
GENERAL  SOMATIC  DEATH 

EVERY  highly  organized  living  being  sooner  or  later  dies  and  thus 
death  is  really  a  physiological  phenomenon.  In  a  large  number  of 
cases,  however,  death  is  premature,  the  outcome  of  disease  and 
therefore,  pathological.  A  sharp  dividing  line  between  physiological, 
and  pathological  death  does  not  exist  for  the  reason  that  the 
physiological  phenomena  and  changes  of  life  which  with  advancing 
age  initiate  and  lead  to  death  are  closely  related  to  those  which 
occur  in  disease.  Death  is  due,  therefore,  either  to  the  physiological 
result  of  aging,  or  to  a  sudden  interference  with  essential  proc- 
esses of  life  which  annihilates  the  orderly  coordination  of  those 
organs  which  form  the  necessary  basis  for  the  individual  unit. 

The  first  problem  which  presents  itself  in  this  connection  is  the 
question  of  what  is  meant  by  general  death?  An  individual  is  dead 
when  all  his  functions  have  been  permanently  abolished.  But  when 
we  investigate  this  further,  we  find  that  this  abolition  of  function  is 
never  sudden,  never  involves  all  organs  or  tissues  simultaneously, 
but  is  gradual  and  of  well-defined  sequence.  Tissues  of  highest  dif- 
ferentiation and  latest  phylogenetic  evolution  (nervous  system) 
cease  functioning  first;  those  of  simplest  differentiation  and  char- 
acter continue  until  much  later.  Thus  brain,  heart  and  respiratory 
actions  are  rapidly  extinguished;  intestinal  peristalsis,  muscular 
irritability  and  certain  secretory  functions  outlast  them  for  hours. 
It  follows,  therefore,  that  an  individual  is  not  completely  dead  until 
considerable  and  variable  time  has  elapsed  since  brain,  heart  and 
respiration  have  ceased  activity.  It  is,  on  the  other  hand,  plain  that 
permanent  stoppage  of  nervous  central  control,  of  heart  action  and 
respiration  is  necessarily  followed  by  death  of  all  tissues  because 
all  irritability,  nutrition  and  organ  interrelations  are  thereby  for- 
ever extinguished.  Thus  a  person  may  be  regarded  as  dead  as  soon 
as  either  brain,  heart  or  lungs  have  ceased  to  activate  and  it  has 

326 


GENERAL  SOMATIC  DEATH        3:27 

become  customary  to  speak  of  brain,  heart  or  lung  death  as  ex- 
pressing the  manner  and  method  through  which  death,  as  it  were, 
entered.  The  "atria  mortis"  of  the  older  writers. 

Very  shortly  after  cessation  of  all  nervous  control  and  circulation, 
appear  other  external  evidences  of  death.  The  body  blanches,  cools 
(algor  mortis)  and  after  a  variable  time  (generally  from  one  to 
several  hours)  there  appears  a  characteristic  post-mortem  lividity 
in  dependent  parts.  This  is  a  bluish,  diffuse  reddening  of  the  skin 
which  depends  upon  the  flow  of  now  stagnant  blood  into  veins  and 
capillary  districts,  following  gravity.  Its  extent  and  occurrence 
depends  upon  the  blood  contents  during  life.  It  occurs  early,  and  is 
more  pronounced  in  plethoric  individuals,  it  is  late  and  fainter  in 
anemic,  emaciated  and  cachectic  subjects.  (An  incision  into  the  skin 
shows  the  blood  in  veins,  never  outside,  an  important  point  in 
distinction  from  ante-mortem  contusions.)  It  is  also  important 
to  remember  that  blood  after  death  flows  from  the  arteries  into 
the  veins.  The  former  are,  therefore,  empty. 

Sooner  or  later  appears  "rigor  mortis,"  an  increasing  stiffness 
and  contraction  of  muscles.  It  commences  in  the  heart  (especially 
in  the  muscular  left  ventricle)  and  then  attacks  the  skeletal  mus- 
cles in  definite  sequence:  jaws  (masseter),  knees,  elbows.  It  is  only 
slight  or  absent  in  non-striated  muscles.  Time  of  its  occurrence 
and  severity  of  the  rigor  vary  greatly  (from  minutes  after  death  to 
hours)  and  depend  upon  a  number  of  factors.  It  takes  place  rapidly 
and  is  strong  in  healthy,  muscular  subjects  which  are  suddenly 
overtaken  by  death  (accident,  rapidly  fatal  infection).  In  anemic, 
emaciated,  cachectic  individuals  who  have  been  ill  of  long  con- 
tinued chronic  disease  it  appears  late  and  is  slight.  Under  these 
conditions  it  may  even  be  entirely  absent.  The  cause  of  the  rigor 
mortis  is  coagulation  of  myosinogen  to  solid  myosin.  This  was 
originally  thought  to  be  due  to  ferment  or  enzyme  action.  Recent 
investigations  have  not  been  able  to  substantiate  this  view.  It  is 
intimately  connected  with  acid  production  in  dead  muscle  and 
seems  to  depend  upon  acid  colloidal  swelling  of  muscle  protoplasm. 
Loss  of  rigor  takes  place  in  proportion  to  its  occurrence  and  severity 
and  seems  to  depend  upon  autolytic  changes  which  diminish  the 
hydrophylic  tendency  of  cells  and  gradually  dissolve  the  coagulated 


328  GENERAL  PATHOLOGY 

proteins.  It  is  usually  coincident  with  the  appearance  of  putrefac- 
tive changes  which  inaugurate  the  final  disintegration  of  cells  and 
tissues. 

Early  in  death  the  cornea  of  the  eye  loses  its  luster,  the  tension 
of  the  whole  eyeball  diminishes  and  the  eye  recedes  in  the  orbit. 
This  is  largely  the  result  of  water  evaporation.  The  sclera  shows 
early  decomposition  spots. 

Putrefaction  shows  itself  first  on  the  surface  of  the  gut  in  a 
greenish  discoloration,  then  on  the  surface  of  those  organs  which 
are  in  close  contact  with  it  (liver,  spleen,  finally  abdominal  wall 
and  muscles).  It  depends  upon  disintegration  of  blood-coloring 
matter  by  putrefactive  intestinal  bacteria  which  in  death  gain 
the  upper  hand,  such  as  saprophytes,  and  is  due  to  the  formation 
of  Fe  sulphide  from  hemoglobin.  In  severe  septic  infections  with 
much  hemolysis,  and  in  plethoric  individuals,  decomposition  may 
commence  almost  immediately  after  death.  It  is,  of  course,  accom- 
panied by  gas  formation  (post-mortem  emphysema)  with  charac- 
teristic odor,  ultimately  the  abdomen  perforates  and  all  oft 
parts  fuse  into  a  humus-like  mass. 

The  final  question  which  presents  itself  is  the  nature  and  signifi- 
cance of  death?  Why  do  we  die?  Apart  from  its  philosophical 
and  metaphysical  interest  this  is  a  matter  of  biological  importance. 

Death  is  not  necessarily  inherent  in  living  matter.  Weismann  has 
pointed  out  that  single-celled  organisms  are  potentially  immortal. 
Death  in  them  is  either  accidental  or  determined  by  the  duration 
of  catabolism  over  anabolism.  If  destructive  metabolic  changes 
gain  ascendency  over  constructive  ones  at  an  early  period,  the 
organism  is  short  lived.  This  is  the  case  in  paramecium  which 
Woodruff  has  cultivated  in  more  than  3000  generations  without 
conjugation  or  loss  of  vitality.  Woodruff  found  that  the  most  im- 
portant factors  for  maintaining  vigor  are  proper  food  and  freedom 
from  poisonous  waste  products.  But  here  an  important  point  must 
be  emphasized;  in  these  and  similar  low  unicellular  organisms  divi- 
sion is  almost  immediately  followed  by  an  organism  exactly  like 
the  parent,  that  is,  differentiation  remains  at  the  lowest  level.  The 
two  resulting  organisms  are  alike  immediately  after  division.  It  is 
not  followed  by  further  differentiation.  In  metozoa,  on  the  other 


GENERAL  SOMATIC  DEATH  329 

hand,  cells,  as  they  divide,  differentiate  themselves  and  thus  a 
simple  protoplasm  is  gradually  replaced  by  products  of  differentia- 
tion, and  becomes  what  is  spoken  of  as  metaplasm.  In  other  words, 
in  the  lowest  forms  of  life,  as  in  the  protozoa,  protoplasm  remains 
labile,  is  never  fixed.  The  adjustment  of  internal  and  external  condi- 
tions, the  regulation  of  catabolism  and  anabolism  is  simple  and 
easily  accomplished.  Thus  even  in  the  highest  metazoa  we  find  the 
power  of  vegetative  regulation  greatest  when  young;  it  gradually 
declines  in  the  individual  as  in  the  phylogenetic  evolution. 

Progressive  evolution  and  differentiation  are  followed,  therefore, 
by  progressive  loss  of  power  of  regulation  in  cell  life,  and  the  higher 
the  differentiation  the  greater  the  loss  in  internal  and  external 
adjustment.  It  is  held  for  these  reasons  by  leading  biologists  of  this 
generation,  more  especially  Minot,  Conklin  and  Child,  that  senes- 
cence is  essentially  a  phenomenon  of  differentiation  and  is  brought 
about  by  the  gradual  ascendency  of  catabolic  over  anabolic  proc- 
esses. Minot  particularly  has,  in  a  very  beautiful  and  ingenious 
way,  developed  these  thoughts  and  emphasized  that  senescence 
and  death  overtake  cells  of  the  individual  organism  very  unequally, 
and  that  man  passes  through  the  most  important  and  rapid  stages 
of  aging  during  his  embryonic  and  infantile  periods. 

After  puberty  senescence  is  relatively  slow  and  protracted. 
Thus  the  so-called  polar  bodies  die  rapidly;  cartilage  and  bone 
may,  in  a  way,  be  regarded  as  degenerated  fixed  tissues;  and  during 
early  life  many  tissues,  like  the  thymus  and  lymphoid  structures, 
degenerate  and  are  gradually  eliminated. 

But  what  causes  differentiation?  Here  I  would  put  forward  the 
idea  that  differentiation  is  the  result  of  integrative  cell  action. 
Combination  of  cells  leads  to  differentiation  and  thus  to  an  or- 
ganic unit.  Cells  do  not  differentiate  themselves  by  their 
own  activities,  but  through  relation  to,  and  influence  of, 
others.  A  single,  independent,  highly  differentiated  cell  is 
unimaginable.  But  this  cell  integration  which  has  gradually  de- 
veloped and  shaped  life  to  the  complicated,  highly  unstable  body 
of  man,  is  not,  as  we  have  had  repeatedly  occasion  to  note,  only  of 
altruistic  but  distinctly  antagonistic  nature.  Development  and 
differentiation  express  activity,  or,  in  a  nai've,  personal  sense, 


330  GENERAL  PATHOLOGY 

struggle,  of  opposing  forces  and  functions  within  the  individual 
unit  of  cells,  and  as  rebuilds  up,  so  it  constantly  breaks  down. 
The  individual  mirrors  the  life  and  evolution  of  his  race.  Differ- 
entiation and  destruction  are,  therefore,  really  correlated.  One  is 
not  well  possible  without  the  other.  Thus  a  complex,  fluid  animal 
organism  has  finally  evolved  out  of  many  interrelated,  unstable 
and  never  perfectly  balanced  cell  territories,  upon  which,  com- 
bined to  from  a  unit,  the  personal  individuality  depends.  Within  this 
unit  regressive  and  progressive  cell  and  tissue  changes  constantly 
proceed  with  corresponding  changes  in  their  .relations.  Age  and 
senility  in  metazoa  are,  therefore,  not  only  the  anatomical  ex- 
pressions of  cell  and  tissue  changes,  but  of  a  necessarily  gradually 
increasing  diversion  in  organ  relations  which  finally  ends  in  rupture, 
that  is,  death.  It  is  the  integration  of  cells  which  creates  higher  life, 
but  also  dooms  it  to  destruction.  Upon  cell  integration  depends  the 
development  and  formation  of  the  whole  animal  organism;  and 
by  continued,  partly  altruistic,  partly  antagonistic,  cell  inter- 
relations, it  leads  the  organism  through  the  various  age  periods 
to  senility  and  death. 

Added  to  these  inherent  factors  is  the  general  tendency  of  ex- 
ternal environment  to  reduce  and  oxidize  complex,  unsaturated,  to 
simple,  saturated  compounds.  By  the  action  of  heat  waves,  through 
cleavage  and  oxidation,  complicated,  unsaturated  products  of  dif- 
ferentiation are  again  broken  down  and,  by  satisfying  their  chemical 
affinities,  are  reduced  to  simpler  compounds  to  re-enter  evolution. 

Thus  we  may  conclude  that  death  in  metazoa  is  really  the  neces- 
sary outcome  of  integrative  cell  action  which  first  creates  and  then 
destroys  differentiation  and  gradually  eliminates  cell  lability.  It  is 
aided  by  the  general  environmental  influences  which  constantly 
tend  to  reduce  complex,  unstable  compounds  to  simple,  stable 
substances. 

Thus  the  old  "Media  Vita  in  morte  sumus"  is  literally  and 
scientifically  true.  While  we  are  living,  we  are  dying,  and  life  and 
death  are  not  antithesis. 

TravTa  set  said  the  ancient  Greek  philosopher  Heraklitus:  "Every- 
thing flows,  is  unfixed,  in  motion."  Life  and  death  are  both  expres- 
sions of  this  movement. 


EPICRISIS 

An  attempt  has  been  made  in  the  foregoing  pages  to  present  and 
lay  bare  pathological  phenomena  in  their  general  characters  and 
relations  and  to  group  them  in  categories  more  or  less  without 
regard  to  their  occurrence  in  a  particular  organ.  The  field  is  vast, 
complex  and,  like  all  human  knowledge,  very  defective.  Moreover 
the  subject  can  be  presented  only  within  this  scope  in  outline.  In 
other  words  the  spade  can  only  be  handed  to  the  reader;  he  must 
himself  do  the  digging.  The  effort  has  been  confined  to  make  it 
clear  that  pathological  processes  (diseases)  are  physical  and  chem- 
ical cell  alterations  and  disturbed  cell  relations  which  follow  com- 
mon biological  laws,  and  in  the  majority  of  instances,  at  least,  find 
a  definite  anatomical  expression.  Moreover,  pathological  definitions 
are  nothing  else  than  a  convenient  and  more  or  less  arbitrary 
manner  of  expressing  certain  cell  and  tissue  states,  and  they  have 
no  abstract  value  which  can  stand  by  itself. 

Emphasis  has  been  laid  on  the  anatomical  side  because  of  its 
importance  in  forming  clear  and,  above  everything  else,  reliable 
visual  conceptions  of  pathological  occurrence.  Theory  and  hypo- 
thesis are  not  to  be  neglected.  They  are  useful  and  stimulating  to 
further  research,  but  they  come  and  go.  Sound  anatomical  obser- 
vation remains  true  as  the  lasting  pillar  of  all  scientific  knowl- 
edge, and  visualized,  anatomical  conceptions  furnish  the  most 
reliable  and  satisfactory  understanding  of  cell  functions. 

The  cultivation  of  pathological  anatomy  and  histology  is  to-day, 
as  it  was  in  the  days  of  Morgagni,  Bichat,  Bright  and  Virchow,  the 
essential  foundation  for  the  science  and  practice  of  medicine. 


33i 


INDEX  OF  PERSONAL  NAMES 


Adami,  58 
Addison,  318 
Albrecht,  173,  203,  244 
Anderson,  130 
Arthus,  129 
Aschoff,  1 88,  234,  302 
Auer,  131 
Austin,  307 
Avery,  23 

Bashford,  292,  297 

Bassis,  2 

Bateson,  164 

Baumgarten,  62 

Bayliss,  120,  298,  310,  311 

Bayne-Jones,  302 

Beckman,  307 

Behring,  59,  60,  128 

Besredka,  in,  131 

Best,  190 

Bichat,  331 

Bienstock,  34 

Bier,  127 

Biltz,  134 

Bizzozero,  302 

Boll,  318 

Bellinger,  72 

Bonnet,  288 

Bordet,  115,  116,  134 

Borst,  215,  278 

Bostrom,  73 

Brettonneau,  51 

Brieger,  56 

Bright,  331 

Bruce,  104 

Briicke,  301 

Bruere,  92,  120,  132 

Buchanan,  301 


333 


Buchner,  79,  114 
Bullock,  88,  127 
Bumm,  30 
Biirker,  195 
Butschli,  178,  203 
Buxton,  41 

Calmette,  69 

Cameron,  310 

Carlier,  301 

Carmalt,  276 

Castellani,  104 

Celli,  28 

Chambers,  203 

Charrin,  12 

Chevreuil,  2 

Child,  329 

Clegg,  71 

Clemens,  93 

Coenen,  278 

Cohn,  3 

Cohnheim,  62,   218,   219,   224,   258, 

281,  308 
Coleman,  41 
Conklin,  203,  329 
Councilman,  47 
Cramer,  88,  127 
Crowdy,  74,  282 
Curschmann,  43 

Dale,  309 
Dallera,  129 
Darwin,  164 
Davain,  78 
Demel,  C,  181 
Dochez,  26 
Doderlein,  20 
Donne,  2 
Dopter,  48 


334 


INDEX  OF  PERSONAL  NAMES 


Douglas,  123 
Driesch,  Hans,  287 
Dupuytren,  84 
Dutton,  100,  103,  104 
Duval,  71 

Eberth,  28,  39,  302 

Ehrenberg,  3 

Ehrlich,  10,  60,   118,   130,   133,   139, 

297 

Eizenbrey,  131 
Elser,  32 

Embleton,  13,  19,  no 
Emmerich,  97 
Eppinger,  197 
Erb,  32 
Ernst,  53 
Escherich,  34,  50 
Ewing,  310 
van  Ermengem,  45,  46 

Fehleisen,  18,  21 
Fichtner,  93 
Fischer,  B.,  125,  201 
Fischer,  M.,  182 
Flexner,  29,  47,  94 
Florito,  294 
Fliigge,  114 
Foot,  237 
Forssner,  135 
Fracastor,  i,  101 
Franke,  93 
Frankel,  25,  56,  87 
Fredericq,  301 
Freund,  301 
Friedlander,  49 
Frosch,  107 

Gaffky,  39,  40 
Galenus,  275 
Galeotti,  180 
Garre,  15 
Gartner,  45 
Gay,  131 
Gessard,  23 


Golgi,  105 

Graham,  119 

Grassberger,  92 

Grawitz,  282 

Gregory,  17 

Gross,  127,  154,  158,  187 

Gruber,  37,  39 

Haarland,  297 
Haller,  173 

Hamburger,  H.  J.,  181 
Hammarsten,  301 
von  Hansemann,  291 
Hansen,  70 
Hartsocker,  i 
Harvey,  298 
Harz,  72 
Hauser,  50 
Haycraft,  301 
Hayem,  302 
Heilbrunn,  203 
Heilner,  132 
Helger,  91 
Henderson,  3 1 1 
Henle,  2,  191 
Heraklitus,  330 
von  Herff,  20 
Hericourt,  14,  129 
Herter,  89 
Hertwig,  145 
Hesse,  65  ' 
Hewson,  300 
Hoffman,  2 
Hofmann,  58,  101 
Hofmeister,  191 
Holmes,  20 
Hopkins,  90 
Hunter,  John,  17,  30 

Ichikawa,  295 

Janeway,  H.  H.,  311 
Jenner,  112 
Jensen,  295 


INDEX  OF  PERSONAL  NAMES 


335 


Jobling,  131 
Johne,  72,  73 
Jiirgensen,  25 

Kahlenberg,  312 

Karsner,  307 

Kartulis,  47 

Kast,  315 

Kaufmann,  303 

Keith,  N.  M.,  310 

Kircher,  i 

Kitasato,  40,  82,  84 

Klebs,  3,  28,  52 

Kleine,  104 

Klotz,  191 

Knapp,  99 

Koch,  3,  14,  19,  34,  39,  47,  62,  64, 

67,  68,  77,  78,  79.  86,  95,  96 
Kockel,  237 
KoIIe,  98 
Koppen,  93 
Kossel,  56 
Kretz,  93 
Krummwiede,  68 
Kruse,  47 

Laennec,  62 
Lafleur,  47 
Laidlaw,  309 
Landsteiner,  180 
Lankester,  Ray,  162 
Lave  ran,  104,  105 
van  Leeuwenhoek,  i,  298 
Leichtenstern,  46,  94 
Lewis,  131,  215 
Lister,  3,  301 
Livingston,  104 
Lloyd,  20 1 
Loeb,  200 
Loerve,  94 
Loewe,  93 
Loffler,  55,  75,  107 
Lubarsch,  222 
Lusk,  189 


Macallum,  B.  A.,  163 

Mac  Callum,  W.  G.,  105 

Mac  Cordick,  193 

Mac  Dougal,  202 

Mac  Kenzie,  32 

Mac  Taggart,  303 

Manson,    103,  105 

Marchand,  209,  263,  283,  288 

Marchiafava,  28 

McCIendon,  203 

McKenty,  69 

Meltzer,  311 

Mendel,  166 

Michaelis,  135 

Milne,  319 

Minot,  152,  329 

Moravitz,  302 

Morgagni,  62,  331 

Morgan,  164,  205 

Much,  64,  67 

Muir,  119 

Murchison,  i,  39 

Murray,  297 

Musgrave,  48 

Nabarro,  104 

Naegeli,  5,  180 

Nauwerck,  94 

Neisser,  30,  32,  52 

NicoIIe,  91 

de  Nittis,  12 

Nocard,  46,  74 

Noeller,  91 

Noguchi,  99,  100,  102,  119 

Novy,  99 

Nuttall,  114 

Obermeier,  98,  323 
Ogsten,  1 6 
Olitsky,  93 
Orgler,  180 
Orth,  52,  250 
Osier,  47 


336 


INDEX  OF  PERSONAL  NAMES 


Park,  54,  68 

Pasteur,  2,  34,  86,  113,  140 

Pearce,  131 

Peters,  319 

Pettenkofer,  97 

Pfeiffer,  28,  29,  33,  39,  97,  114 

Pfuhl,  97 

Pick,  93 

von  Pirquet,  69,  132 

Plenciz,  2 

Plesch,  298 

Plett,  112 

Plotz,  90 

Podwyssotzky,  294 

PoIIender,  78 

Ponfick,  72 

Prowazeck,  91 

Quenu,  310 

Ravant,  48 

Rayer,  75,  78 

Redi,  Francesco,  2 

von  Reklinghausen,  262 

Reinke,  200 

Rhumbler,i24,  125,  203 

Ribbert,  201,  256,  290,  291,  303,  306 

Richet,  14,  129 

Ricketts,  90,  91 

Ricord,  30 

Rindfleisch,  3 

Robbers,  237 

Robertson,  202 

Rocha  Lima,  91 

Rosenau,  129 

Rosenfeld,  189 

Ross,  105 

Roux,  55,  56,  59,  318 

Ruttan,  190 

Salkowski,  190 
SSnger,  283 
Schaudinn,  99,  101 
Schereschewsky,  102 


Schimmelbusch,  302 

Schmidt,  301 

Schultz,  131 

Schultz,  E.  W.,  91 

Schultze,  2 

Schiissler,  91 

Schiitz,  75 

Schwann,  2 

Sellards,  90 

Semmelweiss,  20 

Senator,  52,  324 

Shiga,  47 

Siegel,  101 

Simon,  123    - 

Skoda,  25 

Smith,  Theobald,  10,  66,  129 

Southard,  131 

Spallanzani,  2 

Spemann,  215 

Starling,  315,  3 17 

Sternberg,  242 

Stoeber,  294,  295 

Stoerk,  282 

Strassburger,  165 

Strauss,  94 

Strong,  47,  48,  91 

Sudhoff,  100 

Sylvius,  62 

Tait,  301 
Takaki,  86 
Thiele,  13,  no 
Thiersch,  275 
Thoma,  306 
Tindall,  2 
Toepfer,  91 
Todd,  91,  100,  104 
Tunnecliffe,  98 

Vaughan,  no,  in,  130,  131 
Villemin,  62 
da  Vinci,  Leonardo,  298 
de  Vries  162,  164,  166 


INDEX  OF  PERSONAL  NAMES 


337 


Virchow,  51,  62,  173,  178,  179,  186, 

1 88,  192,  219,  220,  234,  331 
Vogel,  219 
Volkmann,  17 

Wacker,  294,  295 
Wadsworth,  27 
Walbach,  91 
Waldeyer,  3,  276 
Walker,  R.  M.,  119 
Wallace,  A.  R.,  164 
Wallace,  C,  310 
Warthin,  102 
Wassermann,  86,  93 
Weber,  68 

Weichselbaum,  25,  26,  28 
Weigert,  133,  199,  234,  307 
Weigle,  91 
Weismann,  328 


Welch,  87 

Wells,  130,  132,  190 
Wertheim,  31 
Wharton,  183 
Widal,  37,  39,  41 
Wilder,  90 
Willey,  163 
Wilms,  288 
Winternitz,  237 
Woodruff,  328 
Wright,  123 

Yamageiwa,  295 
Yersin,  55,  56,  59,  82 
Young,  42 

Ziegler,  209,  235 
Zillner,  190 
Zinsser,  90 


22 


SUBJECT  INDEX 


Abscesses,  liver  and  subphrenic,  16, 38 

multiple,  1 6,  21,  42 

subcutaneous  and  muscular,  43 

tibial,  43 
Acapnia,  311 
Acid-fast  bacilli,  70 
Acidosis,  association  of  shock  with, 

311 

Acini  in  adenomata,  273 
Acquired  characters,  161 
Acromegaly,  cause  of,  319 

pathological  explanation  of,  204 
Actinomyces,  5,  63,  72,  73 
Actinomycotic  inflammations,  240 
Adaptability  in  bacteria,  1 1 
Addison's  disease,  presence  of  peculiar 
pigmentation  in,  194 

syndrome,    relation    of  suprarenal 

to,  319 

Adenoma  destruens,  281 
Adenomata,  273,  274 
Adipocere,  process  of,  189 
Adrenal,    medulla    of,    as    seat    for 

neuroma  sarcomatodes,  271 
Adrenalin,  discovery  of,  316 
Adsorption  and  fixation,  analysis,  120 

faw,  135 
Aerogenes  capsulatus,  bacillus,  8,  200 

(Welchii)  87 

Afunction  of  internal  secretion,  319 
Agar  serum  of  Wertheim,  3 1 
Age,  disposition  of,  153 

periods  of  change,  153 
Agglutination,  of  bacteria,  122,  134 

specific,  and  optimum  concen- 
tration of  H  ions  for  protein 
precipitation,  analogy  between, 

135 

test  for  bacillus  mallei,  76 


Air  pressure,  141 

Air  and  oxygen,  relation  of,  to  the 

morphology  of  groups  of  bacteria,  9 
Albinos,  198 
Albumen  cell  content  as  differentiation 

in  serous  exudate,  226 
Albuminous  degenerations,  179 
Albuminuria,  143 
"Algor  mortis/*  327 
Allergic,  132 
Amboceptor,  115,  119 
Ameba  coli,  47 
Amitosis,  200,  201,  244 
Amyloid  cell  degeneration,  185 
Anaerobes,  classification  of,  8 

discovery  of,  3 
Anaphylactic  shock,   relation  of,   to 

sudden   death   in  convalescing  in- 
fectious diseases,  132 
Anaphylaxis,  129,  130,  131 

edema  of,  315 

idiosyncrasy  as  a  phase  of,  159 
Anaplasia,  291 
Anasarka,  313 
Anchorage,  bacterial,  112 
Anemia,  89,  139,  299,  300 

compression,  300 

neurotic,  300 

obstruction,  300 

progressive,  299 
Anemias,  fat  infiltration  from,  189 

fatty  disorganization  in,  189 

progressive,  presence  of  hemoglobin 
derivatives  in,  195 

severe,    as  constitutional   effect  of 

malignant  tumors,  249 
Anesthetic  leprosy,  71 
Aneurysm,  aortic,  87 
Aneurysms,  303 


339 


340 


SUBJECT  INDEX 


Angiomata,  246,  284 

hemangiomata,  284 

lymphangiomata,  285 

angiosarcomata,  285 
Angiosarcomata,  285 
Angina  pharyngis,  98 
Anhydremia,  299 
"Animalcules,"  2 
Anisotropic    nature    of    lipoids    or 

phosphatides,  190 

Anopheles  as  a  carrier  of  malaria,  105 
Anthracosis,  198 
Anthrax,  77-80,  109,  113 

bacillus,  4,  8,  9,  13 

susceptibility  of  hens  to,  increased 
by  cold,  140 

symptomatic,  80 
Antiformin,  63 
Antigen,  115,  117 
Antiricine,  122 
Antisepsis,  foundation  of,  3 
Antitoxic  immunity,  character  of,  1 28 
Antitoxines,  51,  59,  60,  128 
Antityphus  serum,  91 
Apoplexy,  261 
Appendicitis,  19 
Apyrexia,  322 
Arsenic  as  toxic  influence  in  edema, 

315 

Arteriosclerosis,  154 
Arthritis,  19,  27,  43 

monoarticular,  32 
Arthus*s  phenomenon  in  anaphylaxis, 

129 

Aspergillus,  74 
Asphyxia  from  electric  current,  144 

from  septicemic  type  of  diphtheria, 

56 

Athrepsia,  297 
"Atria  mortis,"  327 
Atrophy,  176 

and   disuse,    fat   infiltration   from, 
189 

brown,  of  heart  muscle  fibers,  195 


Atrophy,  from  contact  with  amyloid 

cell  degeneration,  186 
of  the  spleen,  156 
Autochthonus,  304 
Autogenous  pigmentation,  194 
Autoplastic  transplantation,  215,  216 
Avian  type  of  tuberculosis,  68 

Babes-Ernst   granules   in  diphtheria 

bacillus,  53 
Bacillus,  aerogenes,  84,  87 

capsulatus,  8,  87,  88,  200 
lactis,  50 

anthrax,  4,  8,  9,  13 

botulinus,  46,  1 1 1 

butter,  69 

chauvei,  81 

cholerae,  4,  8,  9  13,  77-80 

coli,  8,  13,  35,  96,  228 
communior,  34 

diphtheria,  25,  5 1-54,  1 1 1 

dysenteriae,  47,  48 

enteritidis,  45 

fecalis  alkaligenes,  40 

glanders,  9 

gonococcus,  8,  12 

influenzas  12,  25,  26,  92 

mallei,  75 

meningococcus,  12 

mucosus  capsulatus,  49 
characteristics  of,  49 

of  Koch-Weeks,  93 

of  leprosy,  70,  71,  239 

of  malignant   edema,   9,    84,    86, 

87 
of  Pfeiffer,  92 

pathogenicity,  92 
of  tetanus,  9,  in,  127 
paratyphosus,  40,  44,  45 
pest,  optimum  temperature  for,  8 
phlegmones  emphymatosae,  87 
pneumococcus,  12 
proteus  vulgaris,  50 
pyocyaneus,  23 


SUBJECT  INDEX 


Bacillus,  rhinoscleroma,  49 
characteristics,  49 

smegma,  69 

subtilis,  9,  12,  8 1 

tuberculosis,  4,  8,  28,  62-68 

typhoid,  8,  34-36,  39-43.  '35 

typhosus,  34,  39,  4i~43»  47 

xerosis,  58 
Bacteria  3,  4,  5,  7,  1 1 

aSrogenes,  127 
Bacterial  cell,  5,  7 
Bacteriemia,  21,  27,  60,  83,  no 

anthrax,  80 

staphylococcus  as  cause  of,  16 
Bacteriolysis,  115 

Pfeiffer's  phenomenon,  39 
Bacterium  lactis  aerogenes,  34 

mycoides,  13 
Basal  cell  cancers,  279 
Basedow's    disease,    interrelation    of 

thyroid  and  pancreas  in,  320 
Bence  Jones's  body  in  myeloma,  259 
Benign  tumors,  248 
Bile,  method  of  resorption,  196,  197 

pigmentation  in  jaundice,  195 
Bilirubin,  similarity  of  hematoidin  to, 

195,  196 
Bioses,    conversion    of,    into    mono- 

saccharides,  36 
Black  fever,  104 

leg,  80 
Blastomere    derivation    of   embryo- 

mata,  288 

Blastomycosis,  74,  241 
Blood,    and   lymph  vessels,  regener- 
ation of  cells,  207 

circulation,  300 

clotting,  cause  of,  301 

culture  for  streptococci,  21 

pathological  changes  in,  298,  305, 
309,  3io 

poisons,    presence    of    hemoglobin 
derivatives  in,  195 

regeneration  of,  207 


Blood,  thrombosis,  301 

vessels,  autoplastic  transplantation 
of,  216 

Bone  cells,  regeneration  of,  207 
marrow,  154,  192 

Bones  as  point  of  disease  attack  in 
children,  154 

Botulism,  12,  46 

Bovine  type  of  tuberculosis,  68 

Brain   tumors  in   actinomycotic  in- 
flammations, 241 

Brill's  disease,  90 

Bronchitis,  42 

Broncho-pneumonia,  27,  56 

Brownian     movement     of     bacillus 
dysenterise,  48 

Buboes,  32 

Bubonic  plague,  82 

Burns,  137 

Butter  bacilli,  69 

Cachexia,  edema  of,  316 

fatty  disorganization  in,  189 

tumor,  249 

Caffeine  as  a  disturber,  323 
Caisson  disease,  142 
Calcareous  infiltration,  191 
Calcification,  chemical  nature  of,  193 
Calmette,  tuberculin  reaction  of,  69 
Camphor,  osmotic  power  of,  312 
Cancer,  139,  154,  241,  276-281 

from  pathological  scars  due  to 
arrays,  146 

of  breast,  292 

of  the  esophagus  in  Chinamen,  292 

of  the  skin  of  the  abdominal  wall, 
292 

of  uterus,  292 
Cancers,  entodermal  or  ectodermal, 

247 

Cancroids,  280 

Cane  sugar,  osmotic  power  of,  312 
Cantharidin    as    toxic    influence    in 

edema,  315 


342 


SUBJECT  INDEX 


Capillary  circulation,   early  demon- 
stration of,  298 

membranes,  diffusion  permeability 

of,  313 

Capsulated  bacilli,  49 
Capsule  of  bacterial  cells,  7 

of  the  spleen,  155 
Carcinoma  adenomatosum,  281 

origin,  281 

sarcomatodes,  278 
Carcinomata,  276-281 
Carcinosarcomata,  276,  278 
Carriers,  in 

of  bubonic  plague,  83 

of  cholera,  97 

of  diphtheria,  54 

of  dysentery,  48 

of  epidemic  diseases,  127 

of  relapsing  fever,  100 

of  trypansoma  gambiense,  104 

of  typhoid,  42 

of  typhus  fever,  91 

of  Weil's  disease,  100 
Cartilage  tissue  regeneration,  206 
Catarrh,  micrococcus  of,  28,  33 
Catarrhal    inflammation,    Virchow's 

classification  as,  220 
Catarrhal-mucoid  exudate,  226 
Cell,  anatomical  and  functional  unit, 

173 

bacterial,  structure  of,  5 
differentiation,  senescence  a  pheno- 
menon of,  329 

growth  and  repair  of,  201-209 
regression    as    a    preparatory    for 

tumors,  292 

relations,  pathological  changes  in, 
177,  178,  213,  218,  219,  223,  224, 
229,  232,  235,  236,  243 
tumor,  selective  tendency  of,  247 
Cellulitis,     improper    use    of   term, 

226 

Cerebrospinal  meningitis,  28 
Chancre,  239 


Chauveau's  bacillus,  81 

Chemical  nature  of  calcification,  lack 
of  evidence  regarding,  193 

Chemiotaxis,  123,  125,  126,  246 

Chloroma,  269 

Cholera,  95-97 
bacillus,  8,  9,  135 
hog,  45 
spirilla  of,  5 

Chondroma  sarcomatodes,  268 

Chondromata,     combination    of 
fibroma  with,  253 

Cholecystitis,  38,  42 

Cholesterol  as  accelerator  of  tumor 
growth,  202 

Chondroitin  sulphuric  acid,  occa- 
sional admixture  in  amyloid  degen- 
eration, 1 86 

Chordoma,  255,  256 

Chorioepithelioma,  282 

Chorionic  cells  as  the  cause  of 
chorioepithelioma,  282 

Choristomata,  244 

Chromaffinic  system,  318 

Chromatolysis,  in  albuminous  degen- 
erations, 179 

Chromatophores,  194 

Chromatophoroma,  259 

Chromosome  cell  loss,  293 

Chronic  inflammation,  232 

Cicatrization,  tendency  toward,  in 
syhilitic  inflammation,  239 

Circulation,    cessation    of,    as    early 
symptom  of  death,  327 
secondary,  in  infarction,  305 

Circulatory  disturbance,  edema  due 
to,  314 

Cirrhosis,  portal,  197 

Cladothrix,  74 

Coagulation,  cause  of,  301 
necrosis,  199 

Coal-tar  injections,  action  of,  295 

Cocci,  42 

Coccoid  bacilli,  49 


SUBJECT  INDEX 


343 


Cold,  relation  of,  to  life  and  disease, 

139 

Colitis,  infectious,  37,  47,  229 

Colloid  degeneration  of  cells,  183 

Colloidal  nature  of  cells,  124 

Colloidal  relations,  different  expres- 
sions of  laws  of,  135 

Colloids  of  electrolysis,  134 

Colon  ameba,  47 

bacillus,  8,  13,  34~37,  44,  96 
not  agglutinated  by  acids,  135 

Color-blindness,  hereditary  character 
of,  168 

Coma,  143 

Complement,  115,  116,  119 

Congenital,    differentiation    of,  from 

hereditary,  160 
skin  hypertrophy,  204 

Congestion,  venous,  of  the  nervous 
system,  138,  139 

Conjunctivitis,  38,  57,  93 

Connective  tissue,  new  growth  of,  233 
power  of  regeneration  in,  206 
production  in  the  spleen,  156 
tumors  from,  252 

Constitutional  effects  of  tumors,  248 

Contusions,    ante    mortem    differen- 
tiation, 327 

Convergence,  163 

Convulsions,  143 

Copper  oleate,  osmotic  power  of,  312 

Corpora  amylacea,  amyloid  reaction 
of,  1 86 

Corpus    striatum,     center    of    heat 
regulation  in,  324 

Cretinism,  relation  of  thyroid  to,  319 

Croup,  resemblance  of  diphtheria  to, 

51 

Croupous    inflammation,    Virchow's 

classification  as,  220 
Cutaneous  reaction,  von  Pirquet  s, 

69 

Culture  media,  9,  10 
Cystadenomata,  273 


Cystic  glioma,  261 

Cystic  tumors,  physically  similar  to 

colloid  material,  184 
Cystitis,  38,  42 

diphtheritic,    of   urinary    bladder, 

229 
Cytolysis     of     blood     platelets     to 

produce  thrombin,  302 
Cytolytic  necrosis,  199 

Darwinians,  theories  of,  164 
Death,  eye  changes  in,  328 

organs  effected  first,  327 

putrefaction,  328 

somatic,  326 

vitality  of  cell  life,  328,  329 
Defervescence  as  third  stage  of  fever, 

321 
Degeneration   as   a   preparation   for 

metastatic  tumor  growth,  247 

of  cells,  177 

Degenerative  inflammation,  224 
Delirium  from  bacillus  botulinus, 

46 
Depression,  susceptibility  to  cold  in, 

140 
Dermatitis  caused  by  staphylococci, 

15 
Determinants,  relative,  in  streptococci, 

22 
Detoxiating  function  of  the  internal 

secretions,  319 
Dialysis,  312 

of  bacillus  diphtheria,  56 
Diapedesin,  hemorrhage  per,  309 
Diarrheal  diseases  from  bacillus  pro- 

teus,  50 

Diarrheas,  19,  37,  143 
Diatheses,  152 

DifHugia  of  certain  protozoa,  125 
Diffusion  function,  selective  property 

of,  of  capillary  membrane,  313 
Diphtheria,  128 

antitoxine,  122,  129 


344 


SUBJECT  INDEX 


Diphtheria,  bacillus,  5,  12,  51-54 

toxine,  action  of,  on  animals,  109 
Diphtherite,  definition  of,  51 
Diphtheroids,  51,  57,  58,  242 
Diplococcus   intracellularis   meningi- 
tidis,  28 

lanceolatus,  26 

pneumoniae,  25 

characteristics,  25 
Disintegration  pigments,  195 
Dislocation    of   embryonic    cells,    as 

basis  for  tumor  growth,  291 
Disposition,  151,  152 
Dominant  characteristics,   evidences 

of,  167 
Dorset's  egg  medium  in  cultivation  of 

tubercle  bacillus,  65 
Drosophilia  ampelophila,  164 
Drunkards,  action  of  slight  cold  upon, 

140 

Ductless  glands,  function  of,  317 
Dum  dum,  104 
Duodenal  ulcer,  perforation  of,  after 

severe  burns,  138 
Dysentery,  19,  47,  112 
Dysfunction  of  internal  secretion,  319 
Dyspnea  after  inoculation  by  bacillus 
diphtherise,  55 

from  bacillus  botulinus,  46 

Ecchondrosis    clivus    Blumenbachii, 
256 

Ecchymoses,  75,  309 

Edema,  313-316 
in  sunstroke,  138 
inflammatory,  226 

Ehrlich's  theory  of  immunity  based 
on  chemical  properties,  133 

Electricity,  143,  144 

Electrocution,  effects  as  noted  by  ex- 
periment and  autopsy,  144 
procedure  in,  144 

Electrolytes,  action  of,  134 

Elephantiases,  205 


Emboli  (nitrogen)  as  result  of  sudden 

decompression  of  air,  142 
Embolism,  300,  305 

paradox,  306 

results  of,  306 

infarction,  306,  309 

retrograde,  306 
Embolus,  tumor,  248 
Embryomata,  288 

Embryonic,  cells,  presence  of  glyco- 
gen  in,  191 

character,  tumors  of,  245,  246 

rests,  origin  of  tumors  in,  290 
Emphysema,  87,  88,  328 
Empyema,  227 

chronic,  of  the  pleura,  187 
Emulsoids  precipitated  in  albuminous 

degenerations,  182 
Encephalitis,  93 
Encephaloid  tumors,  265 
Enchondroma,  255,  256 
Endocarditis,  19 

Endocrine  glands,  function  of,  317 
Endogenous  pigmentation,  193 
Endometritis,  septic,  20 
Endotheliomata,  283 

angiomata,  284 

angiosarcomata,  285 

hemangiomata,  284 

histoid  or  vascular  type,  284 

lymphangiomata,  285 

organoid  (mesotheliomata),  288 
Endothelium,  purpose  of,  312 
Endotoxine,  definition  of,  43 

lack    of    success    of    antitoxines 

against,  128 
Energetics,  law  of,  120 
Enteritis,  37 

Environment      vs.      congenital      in- 
fluences, 161 
Enzyme  formation,  fermentation  and, 

10 

Epidemic  from  Gartner's  bacillus,  45 
Epinephrin,  317 


SUBJECT  INDEX 


345 


Epistaxis,  308 

Epithelial     cells,     experiments     on 

growth  and  division  of,  201 
glandular  tissue  tumors,  281 
tumors,  experiments  with,  294 
Epithelioid  cells,  237 
Epitheliomata,  279 
Epulis  sarcomata,  266 
Erysipelas,  17,  1 8,  21,  57,  in 
Erythema  multiforme,  18 
Esotoxine,  definition  of,  43 
Etiology  of  tumors,  289 
Evolution,     destructive     and     con- 
structive cycle  of,  330 
Exogenous  pigmentation,  198 
Exophthalmic     goiter,     relation     of 

thymus  to,  320 

Exostoses  in  enchondroma,  256 
Experimental  study  of  tumors,  294 

by  artificial  production,  294 
Exudative    inflammation,  catarrhal- 

mucoid,  226 
croupous,  228 
diphtheritic,  229 
fibrinous,  228 
hemorrhagic,  226 
purulent,  227 
Eye  changes  from  electric  action,  143 

"Farcy"  glanders,  75 

Fastigium,   as  second  stage  of  fever, 

322 
Fatty  metamorphoses,  187 

cholesterinesters,  188 

lipoids  or  phosphatides,  188 

myelins,  188 

neutral  fats,  188 
Febris  continua,  322 

intermittens,  322 

recurrens,  322 

remittens,  322 

Fermentation  and  enzyme  formation, 
10 

cause  of,  3 


Fever,  321-324 

relapsing,  98 
Fibrinous  exudate,  228 

croupous,  228 

Fibroadenoma  intracanaliculare,  274 
Fibroangiomata,  284 
Fibroepithelial  growths,  272 
Fibroma,  252,  253 

combination  of  myxoma  with,  253 

lymphangiectaticum,  253 

molluscum,  253 

sarcomatodes,  268 

telangiectaticum,  253 
Fibromyoma,  260 
Fibrosarcomata,  266 
Fibrous  connective  tissues,  regenera- 
tive power  of,  206 
Filtrable  viruses,  107 
Flexner-Strong  bacillus,  48 
Friedlander's  bacillus,  49 
characteristics  of,  49 
Fungoid  tumors,  264 
Furuncles,  227 
Furunculosis,  227 

Gabbet's  method  for  staining  tuber- 

cule  bacillus,  64 
Gall  stones,  38 
Gametes,  166 
Ganglion  cells,  lack  of  regenerative 

powers  in,  206 
regeneration  of,  208 
Gangrene,  139,  200 

as  secondary  change  in  diphtheritic 

exudate,  229 
Gartner's  bacillus,  45,  46 
Gelatine  to  restore  blood  volume,  311 
Genius,  explanation  of,  168 
Germ  plasm,  persistence  of,  164 
Giant-cell  sarcomata,  266 
Giantism,  cause  of,  319 
Gibbs-Thompson  law  of  energetics, 

1 20 
Glanders,  75,  76,  241 


346 


SUBJECT  INDEX 


Glandular  organs,  regeneration  in,  208 

transplantation,  217 

tumors,  prevalence  of  cachexia  in, 

249 
Glioma,  261,  262 

sarcomatodes,  270 
Glossina  palpalis  as  the  carrier  of 

trypansoma  gambiense,  104 
Glucose  from  glycogen,  relation  of, 

to  diabetes,  320 
Glycerinesters,  188 
Glycogenic  infiltration,  190 
Glycosuria,  relation  of  thyroid  hyper- 

plasia  on  pancreas  in  formation  of, 

320 
Goiter,  relation  of  hypersecretion  to, 

319 

Gonococci     as    cause     of    purulent 

exudate,  228 

Gonococcus,  29,  30,  31,  33 
bacillus,  12 

optimum  temperature  for,  8 
of  Pfeiffer,  28 

Gonorrhea,  30,  32,  in,  127 
Gonorrheal  ophthalmia,  31 
Granulation,   healing  by,  or  second 

intention,  211,  212 
tissue  in  infarcts,  308 

resemblances  of,   to   connective 

tissue  growth,  233 
syphilitic,  239 

Granulomata,  actinomycotic  inflam- 
mations, 240 
blastomycosis,  241 
glanders,  241 
infective,  236,  248,  296 
leprous  inflammations,  240 
rhinosclerma,  241 
syphilitic  inflammations,  239 
tuberculous  inflammations,  236 
Grass  bacillus,  69 
Graves's    disease     accompanied    by 

increased  adrenalin,  320 
relation  of  hypersecretion  to,  319 


Gum  acacia  to  restore  blood  volume, 


H     ion     concentration     in     edema, 

increased,  315 
H2S,  formation  of,  from  peptones  and 

proteins,  9 
Hamartomata,  244 
Hay  bacillus,  69,  81 
Healing  of  inflammation,  23  1 
Heart,  architectural  changes  in,  dur- 
ing various  age  periods,  158 

musculature,  change  in,  from  hya- 
line degeneration,  185 

paralysis  from  sudden  decompres- 

sion of  air,  142 
Heat,    relations   of  to   life    and    to 

disease,  137,  138 
Hemangiomata,  284 
Hematemesis,  309 
Hematoidin,  195 
Hematomata,  309 
Hematoxylon,  185 
Hematuria,  309 

Hemoglobin  derivatives,  193,  195 
Hemoglobinuria,  138 
Hemolysis,  116,  138,  139 
Hemophilia,  168,  310 
Hemoptysis,  309 
Hemorrhage,  309 

from  increased   and  decreased   air 
pressure,    141,  142 

in  central    nervous    system    from 

lightning,  143 
Hemorrhagic  necrosis,  200 

exudate,  226 
Hemosiderin,  195 
Heredity,  159,  160 
Heteroplastic  transplantation,  216 
Heterozygote,  166 
Histamine,  310 
Histogenesis  of  tumors,  289 
Histoid,  sarcomata,  267 

tumors,  244,  252-262 


SUBJECT  INDEX 


347 


Histology  of  tumors,  248 
Hodgkin's  disease,  242,  257 
Hog  cholera,  45 
Homoio-isoplastic      transplantation, 

215,  216 

Homozygotes,  166 
Hormones,  definition  of,  317 
Human  serum,  detection  of,  122 
Hyaline  bodies  in  albuminous  degen- 
erations, 179 

change  in  the  spleen,  155,  156 

degeneration,  184 

sclerosis  of  deep  tissues  caused  by 

x-rays,  146 
Hydrarthros,  313 
Hydremia,  299 
Hydrocephalus,  313 
Hydronephrosis,  200 
Hydropericardium,  313 
Hydrophobia,  84,  113 
Hydrops,  313,  3*5 
Hydrothorax,  313 
Hyperemia,  138,  139 

arterial,  226,  300 

of  organs  from  electric  current,  144 

venous,  300 
Hyperfunction  of  internal  secretion, 

319 

Hypernephroma,  281 

origin  and  growth  of,  282 
Hyperostoses,  257 
Hyperplasia  as  cause  of  plethora  vera, 

298 

differentiation  from  organ  enlarge- 
ment with  actual  cell  alteration, 
204 

inflammatory,     occasional     resem- 
blance of,  to,  243 
leucemic  or  pseudo-Ieucemic,  258 
Hyperplasias,  artificial  tumor  growths 

compared  with,  295 
Hyperthermy,  139 

Hypertrophy,  differentiation  from 
organ  enlargement  with  actual 
cell  alteration,  204 


Hypertrophy,  chemical,  204 

easy  recognition  of,  248 

mechanical,  204 
Hyphomyces,  5,  63,  72 
Hypofunction  of  internal  secretion, 

319 

Hypophysis,  318 
cerebri,     appearance    of    unusual 

lipoma  cells  in,  255 
relation  of,  to  acromegaly,  204 
Hypoplasia,  differentiation  of,  from 

atrophy,  176 
Hysteria,   relation  of  shock  to,  310 


Ichthyosis,  205 
Icterus,  195,  197 

neonatorum,  197 
Immune  serum,  action  of,  134 
Immunity,  108-133 

acquired,  112,  114 

Erhlich's  theory  of,  118 

natural,  109,  114,  126 

passive,  128 

theories  of,  133 

tumor,  297 
Immunization  for  cholera,  98 

of  tubercle  bacillus,  68 
Impetigo  contagiosa,  18 
Incubation  time,  1 1 1 
Indol,  9 
Infarction,  306 
Infection,  historical  consideration,  i 

air  believed  as  medium  of,  I 

contrasted  with  contagion,  i 

discovery  of  bacteria,  2 

discovery    of   larger    micro-organ- 
isms, i,  2 
origin  of,  2 
Infective  granulomata,   difficulty  in 

diagnosis  of,  248 
Inflammation,  acute,  of  spleen,  155 

actinomycotic,  240 

blastomycotic,  241 

course  and  termination  of,  230 


348 


SUBJECT  INDEX 


Inflammation,  definition  of,  235 

degenerative,  223 

exudative,  224 

from  action  of  cold,  139 

glanders,  241 

historical  discussion  of,  220 

infective  granulomata,  236,  240 

interstitial,  221,  232 

leprous,  240 

productive,  229 

rhinoscleroma,  241 

syphilitic,  239 

tuberculous,  239 

unidentified,  242 
Inflammatory  edema,  226,  311,  314 

granulation  tissue,  233,  235 

hydrops,  226 
Influenza  bacillus,  12,  25,  92,  239 

diphtheritic    inflammations    from, 

229 
Infusorial  silica   as   a  stimulant   of 

connective  tissue  formation,  294 
Insolation  by  direct  effect  of  sun's 

rays  on  central  nervous  system,  138 
Integration,     cell,     dependence     of 

development  and  formation  upon, 

330 
Internal  respiration  of  bacteria,  8 

secretions,  154,  316,  318,  319 
Interstitial  inflammations,  221,  232 
Intestinal      catarrh      favors      colon 
bacillus  development,  36 

mucosa,  presence  of  disintegration 

pigments  in,  195 

Intoxication,    chronic,    from    tumor 
products,  249 

fatty  disorganization  in,  189 
Intravenous  fluid  to  restore  blood  to 

circulation  after  shock,  311 
Inulin,  fermentation  of,  by  diplococ- 

cus  pneumonia;,  26 
Irritability,  173 

Irritant,    function    of,    in    upsetting 
the  physiological  cell  emulsion,  182 


Irritants,  pathological,  174 
Irritation  as  accompaniment  of  tumor 
development,  292 

Jaundice,  bile  pigmentation  in,  195, 

hematogenous,  196 

of  the  new-born,  197 

with  relapsing  fever,  99 
Joint  infections,  93,  122 

lesions,  21 

Kala-azar,  104 
Karyokinesis,  200,  201 
Karyorrhexis    in    albuminus    degen- 
erations, 179 
Kataphylaxis  of  Cramer  and  Bullock, 

127 

Kataplasia,  291 
Keloid  form  of  fibroma,  252 
Kidney,  anti-metastatic  tendency  of, 

247 

cell  regeneration  in,  208 
cells,  specificity  of,  174 
susceptibility  of,  182 
changes  in,  during  the  varying  age 

periods,  158 

inflammations,  hyperfunctionation 
of    epithelial     cells     in     early, 

219 

origin  of  cystadenomata  in,  275 
Kidneys,  functioning  of,  with  external 

secretions,  318 
Kieselguhr,  294 
Klebs-Loffler  bacillus,  52 
Koch- Weeks  bacillus,  93 

Lanceolatus  diplococcus,  26 

Law  of  energetics,  Gibbs-Thompson, 

120 
Lecithin   as   a   retardant   of  tumor 

growth,  202 

Leishman-Donovan  trypanosome,  104 
Leprosy,  70,  71 


SUBJECT  INDEX 


349 


Leprous  inflammations,  240 
Leucemia,  lymphatic,  258 
Leucocytes,  identification  of,  220 
formation  of,  207 
presence  of  glycogen  in,  191 
Leucodermia,     absence     of    normal 

pigmentation  in,  198 
Levaditi  silver  method  for  demon- 
strating Spirocheta  pallida,  102 
Leyomyoma,  260 

sarcomatodes,  270 
"Lichtenberg  figures,"  143 
Lightning,  143 
Lipase  for  solution  of  tubercle  bacillus 

capsule,  67 
Lipochromes,  195 
Lipoma,  characteristics,  254 

occasional  combination  of  lymph- 

angiomata  with,  285 
sarcomatodes,  268 
telangiectaticum,  254 
Lipomata,  appearance  of  luteins  in, 

195 
combination  of  fibroma  with,  253 

of  myxoma  with,  253 
renal,  former  classification  of,  282 
Lipoid  solvents,  action  of,  on  normal 
cells    to  produce  parenchymatous 
degeneration,  181 
Lipoids,  119,  126 

agents  dissolving,   as  tumor  irri- 
tants, 295 

degeneration    of,    associated    with 
growth    and    division    of   cells, 

202 

or  phosphatides,  188 
Liquefaction,  199 
Liver,  abscess,  38 

in  amebic  dysentery,  47 
cell  regeneration  in,  208 
cells,  specificity  of,  174 
susceptibility  of,  182 
changes  in,  during  the  varying  age 
periods,  158 


Over,  cytolytic  necrosis  in,  199 
functioning    with    external    secre- 
tions, 318 
origin  of,  cystadenomata  in,  271 

sarcoma,  267 
pigmented   metastases  in  melano- 

sarcoma,  267 
storage  of  sugar  as  glycogen  in, 

190 

Loffler's  bacillus,  57,  68 
Louse,  body,  as  carrier  of  relapsing 

fever,  100 

as  carrier  of  typhus  fever,  91 
Lungs,  susceptibility  of,  to  temper- 

ture  changes,  140 
hemorrhagic,  presence  of  amyloid 

degeneration  in,  187 
Luteins,  195 
Lymphangiomata,  285 
Lymphangitis,  16 
Lymphocytes,  formation  of,  207 
immigration  of,   in  inflammation, 

225 

Lymphoid,  system,  154,  242,  318 
tissue,  tumors  from,  257 
in  the  spleen,  157 
disappearance  of,  152 
instability  of,  154 
Lymphoma,  257 

characteristics,  258 
Lymphogranulomatosis,  242 
Lymphosarcoma,  269 

selective  tendency  of,  247 
Lysis,  cell,  146 

Madura  foot,  74 

Magnesium,    protective    action    of, 

against  bacillus  aerogenes  capsu- 

latus,  87 
Malaria,  104,  105,  107 

as  cause  of  siderosis  in  cells,  194 

cycle  of  fever  in,  323 
Malignant  edema,  86,  87 
bacillus  of,  9 


350 


SUBJECT  INDEX 


Malignant  edema,  tumors,  245,  246 
case  of  spontaneous  healing  of, 

250 

constitutional  effects  of,  249 
Mallein  test  for  glanders,  76 
Malpighian    corpuscle,    construction 

of,  in  the  spleen,  156 
Measles,  57,  107 
Meat  infections  by  bacillus  enteri- 

tidis,  45 

Mediastinitis,  20 
Melanins,  194,  267 
Melanoma,  259 
Melanomata,  251 
Melanotic  sarcoma,  292 
Meningitidis,    diplococcus    intracel- 

lularis,  28 
Meningitis,  94 

epidemic,  29 

tuberculous,  66 
Meningococci,  15,  28 

bacillus,  12 

Menstrual  uterine  mucosa,  152 
Mesonephros,  318 
Mesotheliomata,  285 
Metabolism,  specific,  disturbances  in, 

316 
relation  of  internal  secretions  to, 

319 

Metaplasia,  206,  213,  214 
Metastasis,  244,  245,  246 

inflammatory,  42 
Metritis,  septic,  20 
Metrorrhagia,  309 
Micrococcus,  catarrhalis,  28,  33 

meningitidis,  33 

ureae,  10 

Mitosis,  200,  20 1,  244 
Molds,  74 
"Morbus  gallicus,  the  French  pocks," 

30 

Mortality  from  lightning,  143 
Mosquito  as  a  carrier  of  malaria,  1 05 
Motility  of  bacterial  cells,  5 


Mountain  sickness,  symptoms  of,  141 
Mouse,  susceptibility  of,  to  cancer, 

294 

Mucoid  degeneration,  183 
Mucor-corymbifer,  74 
Mucous  membranes,  susceptibility  of, 

to  temperature  changes,  140 
Muscle  cells,  specificity  of,  174 

fibrils,    swelling   of,    from    hyaline 

degeneration,  185 
regeneration  of,  207 
tissue  derivatives,  260 
Muscles,  storage  of  glycogen  in,  190 
Mushrooms,  similarity  of  botulism  to, 

46 
"Mutants,"     deVries's    experiments 

upon,  163 

Mycoides,  bacterium,  13 
Myelins,  188 

Myeloid  tissue,  tumors  from,  259 
Myeloma,  258 

sarcomatodes,  270 
Myocarditis  in  diphtheria   of  septi- 

cemic  type,  57 
Myoma  sarcomatodes,  270 
Myomata,  260 

Myosinogen,      coagulation     of,      to 
myosin,  as  cause  of  rigor  mortis, 

327 
Myxedemia,   relation  of  thyroid  to, 

319 

Myxoadenomata,    254 
Myxoma,  253,  254 
sarcomatodes,  268 

Necrobiosis,  198 
Necrosis,  16,  198,  199 

of    frontal    bone    of    skull    from 

typhoid  bacillus,  43 
Neisser    staining    for    bacillus   diph- 

theriae,  51 
Nephritis,  132 

chronic,  299 

toxic  edemas  resembling,  315 


SUBJECT  INDEX 


Nervous     system,     action     of,      in 

atrophy,  177 
cessation  of,  as  first  stageof  death, 

327 

pigmentation    of,    from    icterus 
neonatorum,  197 

tissue,  regeneration  of,  207 
tumors  derived  from,  261 
Neural    canal    cells    of   salamander, 

experiments  on  growth  and  division 

of,  20 1 

Neuralgia,  140 
Neurocytoma,  263 
Neurofibromata,  origin  of,  262 
Neuroglia,    function   of,    in   nervous 

system  cell  regeneration,  208 
Neuroma,  262 

sarcomatodes,  271 
Neuropathic  edema,  316 
Neutral  fats,  188 
Nitrates,  reduction  of,  9 
Nitrogen      metabolism,       increased, 

relation  of  hypersecretion  to,  319 
Nitroso  indol  reaction,  96 
Nocardia,  74 
Nodular  leprosy,  71 
Nuclear    division,     relation    of,     to 

protoplasmic  growth,  203 
Nucleus  of  cells,  relation  of,  to  tumor 
development,  293 

resistance  of,  164 
Nutritive  disturbances,  176 

Oligemia,  299 

Opsonins,  123 

Orchitis,  76 

Organ  reconstruction,  inflammatory, 

231 

Organoid  tumors,  244,  271-282 
Osmosis,  312 
Osmotic  pressure  in  edema,  increased, 

314 
Osteoma,  256,  257 

sarcomatodes,  268 


Osteomalacia   as   inducive  to  meta- 

static  calcification,  192 
Osteomata,  combination  of  fibroma 

with,  253 

Osteomyelitis,  15,  43,  110,  154 
Osteosarcoma,  266 
Ovarian  transplantation,  216,  217 
Overnutrition  of  cell,  injurious  effect 

of,  219 
Ovum,  experiments  on  growth  and 

division  of  cells  in,  201 
Oxidation    of    complex     to     simple 

compounds  as  a  factor  in  cell  death, 

330 

Oxygen  and  air,  relation  of,  to  the 
morphology  of  groups  of  bac- 
teria, 9 

pressure,  beneficial  results  of,  141 

Pain  as  cause  of  shock,  3 1 1 
Pancreas,  318 

instability  of,  154 

relation  of,  to  diabetes,  319 

thyroid  action  against,  153 
Papillomata,  272 

Parabiosis,  experiments  of  trans- 
plantation conducted  during,  217 

lack  of  success  in,  216 
Paradox  reaction,  cause  of,  128 
Paralysis,  from  bacillus  botulinus,  46 

diphtheriae,  55 
Paramecium,  127,  328 
Parametritis,  20 
Parasitism,  12 
Paratyphoid  bacillus,  34,  35,  39,  40, 

44,  45 

Parenchymatous  degeneration,  179, 
1 80,  182,  187 

inflammation,  219 

Virchow's  classification  as,  220 

organs,    presence    of    hemoglobin 
derivatives  in,  195 

regeneration  of,  233,  234 
Paresis,  102 


352 


SUBJECT  INDEX 


Passive  immunity,  128 
Pathogenic  protozoa,  103 
Pathogenicity  of  the  tubercle  bacillus, 

65 

Pathological  cell  life,  definition  of,  173 
Periarthritis  from  pneumococci,  27 
Pericarditis,  20 
Periosteum,     new    bone    generated 

from,  207 

Periostitis,  typhoid,  43 
Perithelioma,  285 
Peritonitis,  20,  37 
Pest  bacillus,  optimum  temperature 

for,  8 

Petechiae,  309 
Peyer's  patches,  42 
Pfeiffer's  bacillus,  92 

pathogenicity,  92 
Phagocytosis,  123 
Phenomena  of  surface  tension,   125, 

126 

Phleboliths,  305 
Phlegmon,  21,  227 
Phosphatides,  188 
Phthisis,  62 
Physio-chemical     conditions     inimi- 

cable  to  bacterial  cell  union,  127 
Pia  arachnoid,  inflammation  of,  29 
Pigmentation,  abnormal,  as  evidence 
of  atrophy,  177 

and  pigmentary  degeneration,  193 
Pigmented  tumors,  259 
von  Pirquet's  cutaneous  reaction,  69 
Placenta,  318 

transmission  of  disease  through,  161 
Plague  bacillus,  82 
Plasma,  blood,  constituents  of,  298 
Plasmacytoma,  258 
Plasmodia,  differentiation  of,  106 
Plasmodium  falciparum,  105,  106 

malarias,  105,  106 

vivax,  105 

Pleomorphism     of     bacillus     tuber- 
culosis, 63 


Plethora,  hydremic,  315 

serosa,  299 

vera,  298 

Pleurisy  in  guinea  pigs  after  inocula- 
tion by  bacillus  diphtherias,  54 
Pleuritis,  20 
Pneumococci,  15 

as  infection  in  tuberculous  inflam- 
mation, 239 
Pneumococcus,  93 

bacillus,  12 

infections,  affinity  of  lung  for,  159 

susceptibility   of   guinea    pigs    to, 

140 

Pneumoenteritis  of  calves,  45 
Pneumonia,  42 

aspiration,  19 

diplococcus,  25 

fever  manifestation  in,  323 
Pneumonic  bacillus  of  Friedlander,  49 

plague,  82 
Poisons,  147 
Poliomyelitis,  107 
Polycythemia  in  high  altitudes,  141 

rubra,  299 
Polydactylism,  169 
Polypnea,  139 

Precipitines,  formation  of,  122 
Pressure,   importance  of,   in  transu- 

dation,  313 

Productive  inflammation,  229 
Progressive  cell  changes,  200 
Proteid    precipitation,    a    suggested 

explanation  of  anaphylaxis,  131 
Proteids   as   disturbers   of  the   heat 

regulating  mechanism,  323 
Protein,   by   parenteral  ingestion   in 
relation  to  anaphylaxis,  131,  132 

decomposition    products,    produc- 
tion  of  cancer-like    growth    by 
injections  of,  295 
Proteus  group  of  bacilli,  50 
Prothrombin,  302 
Protoplasm,  173,  178 


SUBJECT  INDEX 


353 


Protoplasmic  swelling  associated  with 

cell  growth,  202 

Protozoa,  discovery  of  disease,  pro- 
ducing, 4 
Pseudo-carcinosarcomata,  278 

diphtheria,  58 

membranous  exudate,  229 

mucin,  183 
Psittacosis,  46 
Ptomaines,  definition  of,  no 

formation  of,  9 
Puerperal  fever,  20 
Purin  bases,  as  disturbers  of  the  heat 

regulating  mechanism,  323 
Purulent  exudate,  227 

synovitis,  19 

Pus  cells,  identification  of,  220 
Putrefaction  in  somatic  death,  328 
Pyemia,  16,  19,  20,  21,  42,  no 

from  pneumococci,  27 

in  glanders,  76 

Pyknosis,      in      albuminous     degen- 
erations, 179 

of  nucleus,  145 
Pyleitis,  38 
Pyocyaneus  bacillus,  23 

characteristics,  23 
Pyogenes  aurens  (staphylococcus)  14, 

15 

Pyonephritis,  42 

Pyrexia,  321 

Pyridineon  osmosis  septa,  results,  312 

Quarterevil   (symptomatic  anthrax). 

80 
Quinine  as  prophylactic  agent  in  the 

treatment  of  malaria,  107 

Race  disposition,  variations  in,  158 
Rats  as  carriers  of  bubonic  plague,  83 

of  Weil's  disease,  100 
susceptibility  of,  to  cancer,  295 
Receptors,  21 

Red  blood-cell  increase,  cause  of,  141 
23 


von  Recklinghausen's  disease,  262 
Regeneration,  of  blood,  207 
and  lymph  vessels,  207 

of  bone,  207 

of  cells,  205 

of  ganglion  cells,  208 

of  glandular  organs,  208 

of  individual  tissues,  206 

of  muscles,  207 

of  nerve  tissue,  208 
Relapsing  fever,  98 

characteristics,  99 

morphology,  99 

method  of  infection,  99 
Renal  lipomata,  former  classification 

as,  282 

Resistance,     of    animals    to    tumor 
grafts,  297 

of  human  body  to  electric  currents, 

144 
"Rest,"  embryonic,  origin  of  tumors 

in,  290 
Resuscitation,  limits  for,  in  freezing, 

139,  140 
Rhabdomyoma,  261 

sarcomatodes,  270 
Rhexin,  hemorrhage  per,  309 
Rhinoscleroma,  49,  241 
Rickets,  154 
Rigor  mortis,  327 

in  heat  stroke,  139 
from  lightning,  143 

Saprophytism,  12 
Sarcoleucemia,  269 
Sarcoma,  melanotic,  292 

perivascular,  285 
Sarcomata,  263-268 

chondroma  sarcomatodes,  268 

fibroma  sarcomatodis,  268 

giant-cell,  266 

glioma  sarcomatodes,  270 

histoid,  267-268 

in  dogs,  296 


354 


SUBJECT  INDEX 


Sarcomata,  in  fowls,  296 
large-cell,  266 

leyomyoma  sarcomatodes,  270 
lipoma  sarcomatodes,  268 
lymphosarcoma,  269 
melanosarcoma,  266 
myeloma  sarcomatodes,  270 
myxoma  sarcomatodes,  268 
neuroma  sarcomatodes,  271 
osteoma  sarcomatodes,  268 
prevalency     of    hemorrhage     and 

softening  in,  249 
rhabdomyoma  sarcomatodes,  270 
small-cell,  265 
spindle-cell,  266 

Sarcomatous  nature  of  lipoma  from 
embryonic  cellular  origin,  253 

Scar  tissue,  origin  of  tumors  from,  292 

Scarlet  fever,  18,  107,  no 

diphtheritic  inflammations  from, 

229 
exudative  nephritis  in,  315 

Schizomycetes,  5,  72 

Scirrhus  cancer,  277 

Sclerosis,   of  connective  tissue,  from 
x-rays,  146 

Segregation,    principle  of,  in  hered- 
itary transmission,  167 

Sensibilism  of  Besredka,  131 

Septicemia,  21,  25,  27,  37,  43,  83,  no 
staphylococcus  as  cause  of,  16 

Serum,  human,  detection  of,  122 
sickness,  129 
therapy,  51 

Sex  glands,  instability  of,  154 

Sexual  disposition,  variations  in,  158 

Shick  reaction,  61 

Shiga  bacillus,  47,  48 

Shock,  310 

action     of,     in      decreasing     heat 
generation,  138 

Siberian    pest,     Russian    name    for 
anthrax,  77 

Side  chain  theory  of  Ehrlich,  130 


Sinus    formation    in    actinomycotic 

inflammations,  240 
Skin,  appearance  of,  from  lightning 
burn,  143 

effects  of  x-rays  on,  145 
"Sleeping  sickness,"  103 
Smallpox,  107 
Smegma  bacillus,  69 
Smith's  dog  serum  in  cultivation  of 

tubercle  bacillus,  65 
Sodium    chloride,    retention    of,    as 

factor  in  nephritic  edema,  315 
Soil  as  source  of  streptococci,  22 
Specificity,     against    proteid    organ 
extracts,  135 

of  reaction  in  bacterial  adsorption 

or  agglutination,  135 
Spermatozoa,  discovery  of,  2 
Spindle-cell  sarcomata,  266 
Spirocheta,  ictero-hemorrhagica,   100 

pallida,  101,  102 

inflammatory  lesions  of,  239 

refringens,  101 
Spirochetes,  95 
Spirillum,  5,  95 

of  Obermeier,  fever  manifestation 

in,  323 
Spleen,  antimetastatic  tendency,  247 

changes  in,  154-157,  158,  318 

enlargment  of,  in  malaria,  107 

instability  of,    154 
Spleens,  soft  155 
Splenic  fever,  77 

Spore  formation  of  bacterial  cells,  5 
Sporothrix,  74 
Sporozotes,  105 

Standardization  of  antitoxine,  60 
Staphylococci,  14-16,  25,  43,  93 

albus,  15 

as  cause  of  purulent  exudates,  227 

aureus,  15 

urese,  15 
Starvation  as  constitutional  effect  of 

malignant  tumors,  249 


SUBJECT  INDEX 


355 


Stasis,  blood,  in  viscera,  139 
Stenosis,  249 

congenital,  of  the  aorta,  300 
Sterility     produced     by     continued 

exposure  to  x-rays,  145 
Stimulation,  explanation  of  cell,  1 78 
Stomatitis,  98 

Streptococci,    15-23,   25,   43,  56,  66, 
68,93 

as  infection  in  tuberculous  inflam- 
mation, 238 
Streptococcus  mucosus,  26 

former  classification  of,  17 
Streptothrix,  74 

group,     classification     of     actino- 

mycosis  in,  72 
Stroma,  formation  of,  in  tumors,  245 

presence  of  glycogen  in,  191 
Structure  of  bacterial  cells,  5 
Struma  suprarenalis  aberrata,  281 
Sunstroke,  138 
Suprarenal,  function,  absence  of,  as 

cause  of  pigmentation,  194 
gland,   enlargement  of,   in  guinea 
pig,  after  inoculation  by  bacil- 
lus diphtheriae,  54 
loss    of,    followed    by    thymus 

hypertrophy,  204 
Surface  tension  in  cells,  123,  124 

movements   produced    by,    125, 

126 

relation  of,  to  inflammatory  exu- 
dation, 225 
to  cell  division,  203 
Susceptibility    of  cells    to    necrosis, 

199 

Symptomatic  anthrax,  80 
Synanche  contagiosa,  52 
Syphilis,  100,  101,  109 

congenital  character  of,  160 
early  epidemic  of,  I 
presence  of  amyloid  cell  degenera- 
tion in,  1 86 
recognition  of,  29 


Syphilis,  similarity  of  certain  stages 

of,  to  blastomycosis,  240 
spirilla  of,  5 
Syphilitic,  infections,  cheesy  necrosis 

in,  199 

inflammations,  239 
differentiation  between,  and  tuber- 
culous granulation,  240 
progress  of  infection,  239 
Syringomyelia,  261 

Tabes  dorsalis,  102 
Temperature,  as  center  of  heat  regu- 
lation, 324 

in  relation  to  morphology  of  groups 
of  bacteria,  8 

mechanism  controlling,  320 

relation  of,  to  disease,  137-139 

rise  of,  cause  of,  323 
Teratoid  growths,  287 
Teratomata,  286,  287 
Terminations  of  inflammation,   230, 

231 

Testicular  transplantation,  216 
Tetanus  bacillus,  9, 84-86, 109, 127, 128 

neonatorum,  85 

toxine,  122 

similarity  of  botulism  to,  46 
Theories  of  immunity,  133 

chemical,  133 

physical,    colloidal    and   electrical, 

134,  135 
Throat   abscess   in   scarlet   fever   as 

foci  for  streptococci,  18 
as  seat  for  streptococci,  18 
Thrombi,     infective,     in     puerperal 

fever,  20 
Thrombin,  301 
Thrombogen,  302 
Thrombosis,  300,  301-305 
Thymus,  318 

disappearance  of,  152 
hypertrophy,  relation  of,  to  loss  of 
suprarenal  gland,  204 


356 


SUBJECT  INDEX 


Thymus,  relation  of,  to  thyroid  secre- 
tion, 320 
Thyroid,  318 

action  against  pancreas,  153 

gland,  diseases  of,  producing  colloid 
cell  generation,  184 

hyperactivity,  relation  of  the  supra- 
renal gland  secretion  to,  320 

relation  of,  to  thymus  secretion, 
320 

transplants,  216 
Tick,  horse,  as  carrier  of  relapsing 

fever,  100 
Timothy  bacilli,  69 
Tissue,  formation,  inflammatory,  232 

soil,  importance  of,  no 
Tonsils  as  foci  for  streptococci,  18 
Toxic  influences,  edema  due  to,  314 
Toxicology,  147 
Toxines,  51 

Toxoids,  definition  of,  61 
Toxones,  definition  of,  61 
Trabeculse  of  the  spleen,  157 
Transplantation,  214 

of  tumors,  experimentation  upon, 

296 

Transudation,  pathological,  311,  312 
Treponema  pallidum,  101,  102 
Triglycerides,  188 
Trinitrotoluene,  200 

as  toxic  influence  in  edema,  315 
Trychomyces,  74 
Trychomyds,  72 
Trypanosoma  gambiense,  103 

characteristics,  103 

transmission    and    pathogenicity, 

103 
Trypanosome  of  Leishman-Donovan, 

104 

Trypanosomes,  103 
Tsetse  fly  as  a  carrier  of  trypansoma 

gambiense,  103 
Tubercle  bacillus,  5,  28,  75 
Tuberculin,  69 


Tuberculosis,  19,  62-66,  154 

affinity  of  lung  for,  159 

avian  type,  67 

basis  of  Bier's  treatment  of,  127 

bovine  type,  67 

chessy  necrosis  in,  199 

congenital  character  of,  160 

differentiation  of  from  lymphoma, 
257 

immunization,  68 

of  cold-blooded  animals,  68 

of  the  lymph  gland,  differentiation 
of,  from  Hodgkin's  disease,  242 

presence  of  amyloid  cell  degener- 
ation in,  1 86 

pulmonary,  similarity  of  lesions  of 
nocardia  to,  74 

similarity  of  certain  stages  of,  to 

blastomycosis,  241 
Tuberculous,  inflammations,  236 
characteristics  of,  238 

granulation,  differentiation  be- 
tween, and  syphilitic  granu- 
lation, 239 

Tumors,  classifications  of,  241,  250, 
251,  256 

endotheliomata,  283 

etiology  and  histogenesis  of,  289 

histoid,  252,  261 

mixed  embryonic,  286 

organoid,  271 

perivascular,  peculiar  hyaline  ma- 
terial in,  185 

sarcomata,  263 

treatment  by  x-ray  or  radium  for, 

146 

Typhoid,  as  cause  of  purulent  exudate, 
228 

bacilli,  action  of  gelatine  in  agglu- 
tination of,  135 

bacillus,  8,  34,  35,  36,  39~43, 
differentiation  of,  from  para- 
typhoid bacillus,  44 

fever,  37,  39~42,  1 10 


SUBJECT  INDEX 


357 


Typhoid,   infections,   affinity  of  gut 
for,  159 

vaccines,  122 
Typhus,  exanthematicus,  90 

fever,  90 

Ulcer,  199 

Umbilical  cord,  presence  of  mucous 

membrane  in,  183 
Uranium  as  toxic  influence  in  edema, 

315 

Urotropine  as  specific  for  elimi- 
nation of  typhoid  bacilli  from 
urinary  tract,  42 

Urticaria,  315 

Uterine  mucosa,  existence  of  gly- 
cogen  in  premenstrual  period  cells 
of,  191 

Vaccination  against  anthrax,  80 
protective,  113 

Vaquez's  disease,  299 

Variations  and  adaptability  in  bac- 
teria, ii 

Vascular  phenomena  in  inflammation, 
221,  224 

Vasculature  of  spleen  incomplete  at 
birth,  156 

Venous  capillary  pressure  in  edema, 

increased,  314 

congestion  detrimental  to  growth  of 
bacteria,  127 

Verrucose  endocarditis,  16 

Vibrio  of  cholera,  96 

Viscosity  of  cell,  increase  in,  associated 
with  cell  division,  203 


Vincent's  angina,  98 

spirilla  of,  5 
Virchow's  theory  of  cell  'growth  and 

division,  201 
Viruses,  filtrable,  107 

Wassermann  reaction  for  syphilis,  117 
test,  variations  in,  121 

Weigert's    principle    of    cell    regen- 
eration after  injury,  133 

Weil's  disease,  100 

Wharton's  jelly,  physiological  proto- 
type of  myxoma,  253 

Widal  reaction,  39,  41 

Witte's  peptone,  97 

Wolff-Eisner  reaction,  69 

Wool-sorter's  disease,  77 

Wound  fevers,  84 

Wound  healing,  208 

by  "first  intention,"  209 

by  "second  intention,"  209,  210 

Xanthoma,  255 

appearance  of  luteins  in,  195 
X-rays,  action  of,  145 

Yeast,  pathogenic,  as  cause  of  blasto- 

mycosis,  241 
Yeasts,  74 
Yellow  fever,  100 

Zenker's  degeneration,  185 

Ziehl's  solution  for  staining  bacillus 

tuberculosis,  64 
Zygote,  1 66 


PAUL  B.  HOEBER 

67-69  EAST  59TH  STREET 

NEW  YORK 


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